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Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated whether alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion in both male and female mice that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch-clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast-spiking and somatostatin-expressing (SOM+) subtypes of inhibitory neurons in layer V of the orbitofrontal cortex 2 months after injury. These subtypes exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons, respectively. By contrast, the fast-spiking and parvalbumin-expressing interneurons did not show changes in intrinsic excitability or synaptic output, respectively. Impairments in non-fast-spiking/SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.SIGNIFICANCE STATEMENT TBI frequently leads to chronic deficits in cognitive and behavioral functions that involve the prefrontal cortex, yet the maladaptive changes that occur in these cortical microcircuits are unknown. Our data indicate that alterations in subtype-specific inhibitory circuits, specifically vulnerability in the non-fast-spiking/somatostatin-expressing interneurons, occurs in the orbitofrontal cortex in the context of chronic deficits in reversal learning. These neurons exhibit reduced excitability and synaptic output, whereas the other prominent inhibitory population in layer V, the fast-spiking/parvalbumin-expressing interneurons as well as pyramidal neurons are not affected. Our work offers mechanistic insight into the subtype-specific function of neurons that may contribute to mental inflexibility after TBI.
Pubmed ID: 35610049 RIS Download
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This monoclonal targets Intercellular Adhesion Molecule-1 / CD54
View all literature mentionsThis polyclonal targets Rabbit to GFP / Green Fluorescent Protein
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis monoclonal targets Parvalbumin
View all literature mentionsThis polyclonal targets Somatostatin
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on September 23,2022. 02111-1307, USA. Sponsors: ImageJ Mosaic Plug-Ins software presented here was produced at the National Center for Microscopy and Imaging Research at San Diego, which is supported by the National Institutes of Health (NIH) through a National Center for Research Resources program grant P41 RR04050.
View all literature mentionsSoftware used to analyze images obtained from microscope. ZEN Black is software Zeiss uses to run their laser-based instruments.
View all literature mentionsSoftware suite for electrophysiology data acquisition and analysis by Molecular Devices. Used for the control and recording of voltage clamp, current clamp, and patch clamp experiments. The software suite consists of Clampex 11 Software for data acquisition, AxoScope 11 Software for background recording, Clampfit 11 Software for data analysis, and optional Clampfit Advanced Analysis Module for sophisticated and streamlined analysis.
View all literature mentionsMus musculus with name B6.Cg-Gt(ROSA)26Sortm32(CAG-COP4*H134R/EYFP)Hze/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J from IMSR.
View all literature mentionsMus musculus with name STOCK Ssttm2.1(cre)Zjh/J from IMSR.
View all literature mentionsMus musculus with name B6.129P2-Pvalbtm1(cre)Arbr/J from IMSR.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on September 23,2022. 02111-1307, USA. Sponsors: ImageJ Mosaic Plug-Ins software presented here was produced at the National Center for Microscopy and Imaging Research at San Diego, which is supported by the National Institutes of Health (NIH) through a National Center for Research Resources program grant P41 RR04050.
View all literature mentionsThis polyclonal targets Rabbit to GFP / Green Fluorescent Protein
View all literature mentionsSoftware used to analyze images obtained from microscope. ZEN Black is software Zeiss uses to run their laser-based instruments.
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis monoclonal targets Parvalbumin
View all literature mentionsThis polyclonal targets Somatostatin
View all literature mentionsSoftware suite for electrophysiology data acquisition and analysis by Molecular Devices. Used for the control and recording of voltage clamp, current clamp, and patch clamp experiments. The software suite consists of Clampex 11 Software for data acquisition, AxoScope 11 Software for background recording, Clampfit 11 Software for data analysis, and optional Clampfit Advanced Analysis Module for sophisticated and streamlined analysis.
View all literature mentionsMus musculus with name B6.Cg-Gt(ROSA)26Sortm32(CAG-COP4*H134R/EYFP)Hze/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J from IMSR.
View all literature mentionsMus musculus with name STOCK Ssttm2.1(cre)Zjh/J from IMSR.
View all literature mentionsMus musculus with name B6.129P2-Pvalbtm1(cre)Arbr/J from IMSR.
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