Dragoi lab research provides new insight into cortical inactivation manipulations
Recent research from the lab of Valentin Dragoi, PhD, Rochelle and Max Levit Distinguished Professor in the Neurosciences, seeking to understand how the brain generates patterns of activity underlying perception, behavior, and cognition by examining distributed neuronal networks, was published in eLife.
The research, and the paper titled, “Heterogeneous side effects of cortical inactivation in behaving animals,” is a collaboration among the Dragoi lab; John Spudich, PhD, Robert A. Welch Distinguished Chair in Chemistry; Roger Janz, PhD, associate professor in the Department of Neurobiology and Anatomy; and was supported by the NIH Brain Initiative Award given to the trio in 2015.
When explaining the neural bases of behavior, scientists often use inactivation techniques, which permanently or temporarily shut off a specific part of a neural network to understand its contribution to behavior. An assumption about inactivation studies is that the targeted neurons become silent while the surrounding regions of the brain are only impacted slightly.
“In our paper, we challenged this longstanding idea by demonstrating that silencing one part of the network induces complex, unpredictable activity changes in neurons outside the targeted inactivation zone,” Dragoi said. “These off-target side effects complicate interpretations of inactivation manipulations, especially when they are related to changes in behavior.”
The lab’s research studied a chloride-conducting channelrhodopsin, GtACR2, which was expressed for the first time in populations of excitatory cells in the primary visual cortex. The viral construct is sensitive to light and produces hyperpolarizing currents that are stronger than other inhibitory opsins.
The team developed a novel biopsy technique to extract cortical tissues for immunohistochemical analysis. Preclinical models in the study performed a visual detection task, with half the trials in a session associated with optogenetic suppression. Using a moveable fiber optic positioned to inactivate the superficial layers of the primary visual cortex, the lab measured the amount of direct and indirect suppression.
“Contrary to the commonly held assumption that cortical inactivation has a negligible impact on surrounding cortical tissue, our study revealed highly heterogenous changes in neural population responses hundreds of microns away,” said the first author of the study, Ariana Andrei, PhD. “The most surprising effects are the uncovering of response facilitation and mixture of facilitation and suppression in the middle and deep cortical layers of the distal network, with significant consequences for behavioral performance.”
Through the research, the lab discovered that optogenetic cortical inactivation is associated with complex patterns of neural responses around the targeted cortical region. They uncovered heterogenous off-target responses that resulted in heterogeneous changes in behavioral performance. This suggests that mixed off-target effects explain highly variable changes in behavioral performance during cortical inactivation, implying the need for new strategies to limit, or monitor, off-target network effects.
“The findings in this article are part of a much larger, ongoing project in the Dragoi lab seeking a comprehensive understanding of the inner workings of large neuronal networks underlying behavior and cognition,” Dragoi said. “This larger project heavily relies on optogenetic and electrical stimulation in conjunction with massive recordings of neural population activity to selectively activate and inactivate parts of the network involved in key neural computations.”
Contributing authors for the paper are Dragoi; Spudich; Janz; Andrei; Samantha Debes, PhD candidate; Mircea Cherlaru, PhD, research scientist; Xiaoqin Liu, PhD; and Elsa Rodarte, MD, neurology fellow.