Cortical circuitry modification in stress and psychiatric disorders
Updated: Sep 28, 2020
Stress pervades modern life. It is a major risk factor for many psychiatric disorders. As sensorimotor abnormalities are often present in these disorders, and mouse sensory cortices are accessible for in vivo imaging studies, we focused on the somatosensory cortex in the initial investigations. Combining behavioral analyses, chronic synaptic imaging, and cell type-specific manipulations, we explored how stressful experiences affect local cortical circuits. We showed that stress leads to progressive, clustered loss of dendritic spines on pyramidal neurons in the mouse barrel cortex, and that such spine loss closely associates with degraded performance in a whisker-dependent texture discrimination task. We also found that the excitability of one type of inhibitory interneurons, parvalbumin-positive (PV+) interneurons, decreases in stressed mice. Finally, activation of PV+ interneurons in the barrel cortex during stress by pharmacogenetics or behavioral intervention prevents spine loss and behavioral deficiency. These findings suggest that a well-tuned inhibitory circuit is crucial for normal synaptic dynamics in the mouse barrel cortex and sensory function, and that regulation of PV+ interneuron activity is a potential therapeutic target for stress-related disorders.
Currently we are extending our research to the prefrontal cortex (PFC), which connects extensively with many cortical and sub-cortical regions and regulates a variety of higher cognitive functions. Both attentional and memory deficits in human psychiatric patients have been attributed to PFC pathology. In this project, we will ask how distinct PFC circuits are involved in different executive functions. As PFC malfunction is implicated in many psychiatric disorders, this line of research will provide vital information about these diseases and potentially lead to effective therapies.
Chen C-C, Lu J, Yang R, Ding JB and Zuo Y (2018) Selective activation of parvalbumin interneurons prevents stress-induced synapse loss and perceptual defects. Mol. Psych. 23(7):1614-1625
Taking advantage of mouse genetics and in vivo imaging, our earlier studies have also identified multiple molecules, including cell adhesion molecules, signaling molecules, and transcription and translation regulators, which regulate dendritic spine formation, stabilization and elimination. Using them as entry point, we continue to investigate the molecular, cellular, and circuit changes underlying neurological and psychiatric disorders, and exploring potential therapeutic targets.
Djurisic M, Vidal GS, Mann M, Aharon A, Kim T, Santos AF, Zuo Y, Hübener M and Shatz C (2013) Spine density regulated by PirB underlies enhanced cortical plasticity in the presence of increased inhibition. Proc. Nat. Acad. Sci. 110(51):20771-20776
Martin PM, Stanley RE, Ross AP, Freitas AE, Moyer CE, Brumback AC, Iafrati J, Stapornwongkul KS, Dominguez S, Kivimäe S, Mulligan KA, Pirooznia M, McCombie WR, Potash JB, Zandi PP, Purcell SM, Sanders SJ, Zuo Y, Sohal VS, Cheyette BNR (2018) DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling. Mol. Psychiatry 23(2):467-475
Park E, Tjia M, Zuo Y* and Chen L* (2018) Postnatal ablation of synaptic retinoic acid signaling impairs cortical information processing and sensory discrimination in mice. J. Neurosci. 38(23):5277-5288 (*: corresponding authors)