Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Abstract

Background Cerebral cortical GABAergic interneuron dysfunction is hypothesized to lead to cognitive deficits co-morbid with human neuropsychiatric disorders, including schizophrenia, autism and epilepsy. We have previously shown that mice that harbor mutations in the Plaur gene, which is associated with schizophrenia, have deficits in frontal cortical parvalbumin expressing interneurons. Plaur mice have impaired reversal learning, similar to deficits observed in patients with schizophrenia. Methods We examined the role of parvalbumin interneurons in orbitofrontal cortex (OFC) during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analysed during correct and incorrect decision choices and reward receipt. Results Neurons in control mice exhibited strong phasic responses both during discrimination and reversal learning to decisions and rewards, and the strength of the response was correlated with behavioral performance. Although baseline firing was significantly enhanced in Plaur mice, neural selectivity for correct or erroneous decisions was diminished and not correlated with behaviour, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across tasks phases during the decision period. Conclusions These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in OFC. Deficits in inhibition blunt selective neural firing during key decisions, contributing to behavioral inflexibility. These data provide a potential explanation for disorders of cognitive control that accompanies the loss of these GABAergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia.

Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions

“…For example, Schoenbaum et al (2000) performed simultaneous recordings of neurons in LO/VO and basolateral amygdala during an odor discrimination task and observed increases in correlated activity during reversal of an initially established stimulus-outcome association (odor-sucrose). A recent report from Bissonette et al (2014b) also found that LO/VO neurons in the mouse respond to odor discrimination performance, reversal performance, or exclusively with respect to the expected outcome.…”

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…The ability to initiate, select, and shift action involves the ventromedial and orbitofrontal regions of the prefrontal cortex, and the dorsal striatum Hamilton and Brigman 2015). Reversal learning is thought to depend on medial prefrontal cortex, orbitofrontal cortex, and interconnected subcortical areas, most notably dorsal striatum (Ragozzino 2007;Bissonette et al 2008Bissonette et al , 2015Brigman and Rothblat 2008). Deficits in pairwise discrimination and reversal learning in the Dolmetsch 16p11.2+/2 could be a consequence of cortical and striatal defects.…”

Gamma Rhythms Link Prefrontal Interneuron Dysfunction with Cognitive Inflexibility in Dlx5/6+/− Mice

“…However, it is not clear whether the alterations in interneurons observed in schizophrenia cause abnormal γ oscillations and thereby contribute to cognitive deficits, or whether alterations in PV interneurons and γ oscillations represent incidental or compensatory changes. While many studies have found important schizophrenia-related abnormalities in mutant mice with disruptions in cortical GABAergic interneurons (Belforte et al, 2010; Bissonette et al, 2014), including specific disruptions of FSINs (Carlen et al, 2012; Del Pino et al, 2013; Korotkova et al, 2010), none have reported the deficits in task-evoked γ oscillations that are hypothesized to mediate cognitive deficits (it is unclear whether they explicitly looked for and did not find deficient task-evoked γ oscillations). By contrast, NMDAR antagonists can both increase baseline γ oscillations and decrease sensory stimulus-evoked γ power (Saunders et al, 2012).…”