Allen Chen

All Publications

• Opponent control of reinforcement by striatal dopamine and serotonin. Nature Cardozo Pinto, D. F., Pomrenze, M. B., Guo, M. Y., Touponse, G. C., Chen, A. P., Bentzley, B. S., Eshel, N., Malenka, R. C. 2024

  Abstract

  The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning1-8. Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations9-14. However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a mouse model enabling simultaneous genetic access to the brain's DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signaling and decrease 5HT signaling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioral deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive acquisition of new associations and supported reinforcement more potently than either manipulation alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement.

  View details for DOI 10.1038/s41586-024-08412-x

  View details for PubMedID 39586475

• Presentation and Management of Acute Mania in Fanconi-Bickel Syndrome, A Metabolic Genetic Disorder. Case reports in psychiatry Chen, A. P., Russell, G., Ashour, A., Yacoub, A. 2024; 2024: 5593846

  Abstract

  Fanconi-Bickel syndrome (FBS) is a rare metabolic disorder caused by decreased glucose transporter 2 (GLUT2) function due to several known mutations in the SLC2A2 gene. As of 2020, 144 cases of FBS have been described in the literature. Metabolic and somatic sequelae include dysglycemia and accumulation of glycogen in the kidney and liver. However, there are no descriptions in the literature of possible neuropsychiatric manifestations of FBS. This case report is to our knowledge the first in this regard, describing a patient with FBS who was admitted to our psychiatric inpatient unit while experiencing acute mania. We conceptualize the case as a novel psychiatric presentation of acute mania in FBS, which may inform our understanding of bipolar disorder pathophysiology because of the hypothesized functional changes in neural pathways involving the paraventricular thalamus induced by decreased GLUT2 activity in FBS.

  View details for DOI 10.1155/2024/5593846

  View details for PubMedID 38605735

  View details for PubMedCentralID PMC11008969

• Behavioral Impairments and Increased Risk of Cortical Atrophy Risk Scores Among World Trade Center Responders. Journal of geriatric psychiatry and neurology Chen, A. P., Ismail, Z., Mann, F. D., Bromet, E. J., Clouston, S. A., Luft, B. J. 2024; 37 (2): 114-124

  Abstract

  Objective: World Trade Center (WTC) responders are susceptible to both cognitive and neuropsychiatric impairments, particularly chronic posttraumatic stress disorder. The present study examined self-reported behavioral impairments in a sample of 732 WTC responders, 199 of whom were determined to have high risk of WTC-related cortical atrophy by an artificial neural network. Results: We found that responders at increased risk of cortical atrophy showed behavioral impairment across five domains: motivation, mood, disinhibition, empathy, and psychosis (14.6% vs 3.9% in the low-risk group; P = 3.90 × 10-7). Factor analysis models revealed that responders at high risk of cortical atrophy tended to have deficits generalized across all aspects of behavioral impairment with focal dysfunction in sensory psychosis. We additionally describe how relationships are modulated by exposure severity and pharmacological treatments. Discussion: Our findings suggest a potential link between sensory deficits and the development of cortical atrophy in WTC responders and may indicate symptoms consistent with a clinical portrait of parietal dominant Alzheimer's disease or a related dementia (ADRD). Results underscore the importance of investigating neuropsychiatric symptomatology in clinical evaluations of possible ADRD.

  View details for DOI 10.1177/08919887231195234

  View details for PubMedID 37542409

  View details for PubMedCentralID PMC10839111

• Nigrostriatal dopamine modulates the striatal-amygdala pathway in auditory fear conditioning. Nature communications Chen, A. P., Chen, L., Shi, K. W., Cheng, E., Ge, S., Xiong, Q. 2023; 14 (1): 7231

  Abstract

  The auditory striatum, a sensory portion of the dorsal striatum, plays an essential role in learning and memory. In contrast to its roles and underlying mechanisms in operant conditioning, however, little is known about its contribution to classical auditory fear conditioning. Here, we reveal the function of the auditory striatum in auditory-conditioned fear memory. We find that optogenetically inhibiting auditory striatal neurons impairs fear memory formation, which is mediated through the striatal-amygdala pathway. Using calcium imaging in behaving mice, we find that auditory striatal neuronal responses to conditioned tones potentiate across memory acquisition and expression. Furthermore, nigrostriatal dopaminergic projections plays an important role in modulating conditioning-induced striatal potentiation. Together, these findings demonstrate the existence of a nigro-striatal-amygdala circuit for conditioned fear memory formation and expression.

  View details for DOI 10.1038/s41467-023-43066-9

  View details for PubMedID 37945595

  View details for PubMedCentralID PMC10636191

• Lysine Ubiquitylation Drives Rhodopsin Protein Turnover. Advances in experimental medicine and biology Chen, A. P., Chea, L., Lee, E. J., Lin, J. H. 2023; 1415: 493-498

  Abstract

  Rhodopsin is a G-protein-coupled receptor that is specifically and abundantly expressed in rod photoreceptors. Over 150 rhodopsin mutations cause autosomal dominant retinitis pigmentosa (adRP). The most common mutation in the United States is the conversion of proline to histidine at position 23 (P23H) in the N-terminal domain of rhodopsin. We previously found that P23H rhodopsin was misfolded, ubiquitinylated, and rapidly degraded. Here, we investigated the role of lysine residues on P23H rhodopsin ubiquitinylation and turnover. We transfected HEK293 cells with a P23H human rhodopsin construct where all 11 lysine residues were mutated to arginine (K-null P23H). We found that the K-null P23H rhodopsin was significantly less ubiquitylated than intact P23H rhodopsin. We found that K-null P23H protein turnover was significantly slower compared to P23H rhodopsin through cycloheximide chase analysis. Finally, we also generated a wild-type rhodopsin construct where all lysines were converted to arginine and found significantly reduced ubiquitylation. Our findings identify ubiquitinylation of lysine residues as an important posttranslational modification involved in P23H rhodopsin protein degradation.

  View details for DOI 10.1007/978-3-031-27681-1_72

  View details for PubMedID 37440077

  View details for PubMedCentralID 4627472

• Nigrostriatal dopamine pathway regulates auditory discrimination behavior. Nature communications Chen, A. P., Malgady, J. M., Chen, L., Shi, K. W., Cheng, E., Plotkin, J. L., Ge, S., Xiong, Q. 2022; 13 (1): 5942

  Abstract

  The auditory striatum, the tail portion of dorsal striatum in basal ganglia, is implicated in perceptual decision-making, transforming auditory stimuli to action outcomes. Despite its known connections to diverse neurological conditions, the dopaminergic modulation of sensory striatal neuronal activity and its behavioral influences remain unknown. We demonstrated that the optogenetic inhibition of dopaminergic projections from the substantia nigra pars compacta to the auditory striatum specifically impairs mouse choice performance but not movement in an auditory frequency discrimination task. In vivo dopamine and calcium imaging in freely behaving mice revealed that this dopaminergic projection modulates striatal tone representations, and tone-evoked striatal dopamine release inversely correlated with the evidence strength of tones. Optogenetic inhibition of D1-receptor expressing neurons and pharmacological inhibition of D1 receptors in the auditory striatum dampened choice performance accuracy. Our study uncovers a phasic mechanism within the nigrostriatal system that regulates auditory decisions by modulating ongoing auditory perception.

  View details for DOI 10.1038/s41467-022-33747-2

  View details for PubMedID 36209150

  View details for PubMedCentralID PMC9547888

• YY Lysine Ubiquitylation in P23H Rhodopsin Protein Degradation Chea, L., Chen, A., Chan, P., Lee, G., Lin, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401305307

• A deep learning approach for monitoring parietal-dominant Alzheimer's disease in World Trade Center responders at midlife. Brain communications Chen, A. P., Clouston, S. A., Kritikos, M., Richmond, L., Meliker, J., Mann, F., Santiago-Michels, S., Pellecchia, A. C., Carr, M. A., Kuan, P. F., Bromet, E. J., Luft, B. J. 2021; 3 (3): fcab145

  Abstract

  Little is known about the characteristics and causes of early-onset cognitive impairment. Responders to the 2001 New York World Trade Center disaster represent an ageing population that was recently shown to have an excess prevalence of cognitive impairment. Neuroimaging and molecular data demonstrate that a subgroup of affected responders may have a unique form of parietal-dominant Alzheimer's Disease. Recent neuropsychological testing and artificial intelligence approaches have emerged as methods that can be used to identify and monitor subtypes of cognitive impairment. We utilized data from World Trade Center responders participating in a health monitoring program and applied a deep learning approach to evaluate neuropsychological and neuroimaging data to generate a cortical atrophy risk score. We examined risk factors associated with the prevalence and incidence of high risk for brain atrophy in responders who are now at midlife. Training was conducted in a randomly selected two-thirds sample (N = 99) enrolled using of the results of a structural neuroimaging study. Testing accuracy was estimated for each training cycle in the remaining third subsample. After training was completed, the scoring methodology that was generated was applied to longitudinal data from 1441 World Trade Center responders. The artificial neural network provided accurate classifications of these responders in both the testing (Area Under the Receiver Operating Curve, 0.91) and validation samples (Area Under the Receiver Operating Curve, 0.87). At baseline and follow-up, responders identified as having a high risk of atrophy (n = 378) showed poorer cognitive functioning, most notably in domains that included memory, throughput, and variability as compared to their counterparts at low risk for atrophy (n = 1063). Factors associated with atrophy risk included older age [adjusted hazard ratio, 1.045 (95% confidence interval = 1.027-1.065)], increased duration of exposure at the WTC site [adjusted hazard ratio, 2.815 (1.781-4.449)], and a higher prevalence of post-traumatic stress disorder [aHR, 2.072 (1.408-3.050)]. High atrophy risk was associated with an increased risk of all-cause mortality [adjusted risk ratio, 3.19 (1.13-9.00)]. In sum, the high atrophy risk group displayed higher levels of previously identified risk factors and characteristics of cognitive impairment, including advanced age, symptoms of post-traumatic stress disorder, and prolonged duration of exposure to particulate matter. Thus, this study suggests that a high risk of brain atrophy may be accurately monitored using cognitive data.

  View details for DOI 10.1093/braincomms/fcab145

  View details for PubMedID 34396105

  View details for PubMedCentralID PMC8361422

• Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease. Biomedicines Chen, A. P., Chen, L., Kim, T. A., Xiong, Q. 2021; 9 (6)

  Abstract

  Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson's, Schizophrenia, addiction, and Alzheimer's disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA's behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia's dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA's reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson's disease, addiction, and Alzheimer's Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA's necessity and contribution to the functional plasticity of different striatal regions.

  View details for DOI 10.3390/biomedicines9060647

  View details for PubMedID 34200134

  View details for PubMedCentralID PMC8228225

• Genetic targeting of astrocytes to combat neurodegenerative disease. Neural regeneration research Kery, R., Chen, A. P., Kirschen, G. W. 2020; 15 (2): 199-211

  Abstract

  Astrocytes, glial cells that interact extensively with neurons and other support cells throughout the central nervous system, have recently come under the spotlight for their potential contribution to, or potential regenerative role in a host of neurodegenerative disorders. It is becoming increasingly clear that astrocytes, in concert with microglial cells, activate intrinsic immunological pathways in the setting of neurodegenerative injury, although the direct and indirect consequences of such activation are still largely unknown. We review the current literature on the astrocyte's role in several neurodegenerative diseases, as well as highlighting recent advances in genetic manipulation of astrocytes that may prove critical to modulating their response to neurological injury, potentially combatting neurodegenerative damage.

  View details for DOI 10.4103/1673-5374.265541

  View details for PubMedID 31552885

  View details for PubMedCentralID PMC6905329