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Research Articles, Systems/Circuits

Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion

Amber L. Nolan, Vikaas S. Sohal and Susanna Rosi
Journal of Neuroscience 6 July 2022, 42 (27) 5361-5372; DOI: https://doi.org/10.1523/JNEUROSCI.0097-22.2022
Amber L. Nolan
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98104
2Departments of Pathology
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Vikaas S. Sohal
3Psychiatry, and
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Susanna Rosi
4Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, California 94143
5Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, California 94143
6Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143
7Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, California 94143
8Kavli Institute of Fundamental Neuroscience, University of California, San Francisco, San Francisco, California 94143
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Abstract

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.

  • disinhibition
  • optogenetics
  • orbitofrontal cortex
  • selective vulnerability
  • somatostatin inhibitory neurons
  • traumatic brain injury

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The Journal of Neuroscience: 42 (27)
Journal of Neuroscience
Vol. 42, Issue 27
6 Jul 2022
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Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion
Amber L. Nolan, Vikaas S. Sohal, Susanna Rosi
Journal of Neuroscience 6 July 2022, 42 (27) 5361-5372; DOI: 10.1523/JNEUROSCI.0097-22.2022

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Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion
Amber L. Nolan, Vikaas S. Sohal, Susanna Rosi
Journal of Neuroscience 6 July 2022, 42 (27) 5361-5372; DOI: 10.1523/JNEUROSCI.0097-22.2022
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Keywords

  • disinhibition
  • optogenetics
  • orbitofrontal cortex
  • selective vulnerability
  • somatostatin inhibitory neurons
  • traumatic brain injury

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