Behavioral flexibility is associated with changes in structure and function distributed across a frontal cortical network in macaques

One of the most influential accounts of central orbitofrontal cortex– that it mediates behavioral flexibility – has been challenged by the finding that discrimination reversal in macaques –the classic test of behavioral flexibility –is unaffected when lesions are made by excitotoxin injection rather than aspiration. This suggests the critical brain circuit mediating behavioral flexibility in reversal tasks lies beyond the central orbitofrontal cortex. To determine its identity a group of nine macaques were taught discrimination reversal learning tasks and its impact on grey matter was measured. Magnetic resonance imaging scans were taken before and after learning and compared with scans from two control groups each comprising ten animals. One control group learned similar discrimination tasks but which lacked any reversal component and the other control group engaged in no learning. Grey matter changes were prominent in posterior orbitofrontal cortex/anterior insula but also were found in three other frontal cortical regions: lateral orbitofrontal cortex (12o), cingulate cortex, and lateral prefrontal cortex. In a second analysis, neural activity in posterior orbitofrontal cortex/anterior insula was measured at rest and its pattern of coupling with the other frontal cortical regions was assessed. Activity coupling increased significantly in the reversal learning group in comparison to controls. In a final set of experiments we used similar structural imaging procedures and analyses to demonstrate that aspiration lesion of central orbitofrontal cortex, of the type known to affect discrimination learning, affected structure and activity in the same frontal cortical circuit. The results identify a distributed frontal cortical circuit associated with behavioral flexibility.

The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges

Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer’s disease (AD). To develop novel therapies, it is beneficial to explore this specific aspect of cognition preclinically. The location discrimination reversal (LDR) task is a hippocampal-dependent operant paradigm that evaluates spatial learning and cognitive flexibility using touchscreens. Here we assessed baseline performance as well as multimodal disease-relevant manipulations in mice. Mice were trained to discriminate between the locations of two images where the degree of separation impacted performance. Administration of putative pro-cognitive agents was unable to improve performance at narrow separation. Furthermore, a range of disease-relevant manipulations were characterized to assess whether performance could be impaired and restored. Pertinent to the cholinergic loss in AD, scopolamine (0.1 mg/kg) produced a disruption in LDR, which was attenuated by donepezil (1 mg/kg). Consistent with NMDA hypofunction in cognitive impairment associated with SZ, MK-801 (0.1 mg/kg) also disrupted performance; however, this deficit was not modified by rolipram. Microdeletion of genes associated with SZ (22q11) resulted in impaired performance, which was restored by rolipram (0.032 mg/kg). Since aging and inflammation affect cognition and are risk factors for AD, these aspects were also evaluated. Aged mice were slower to acquire the task than young mice and did not reach the same level of performance. A systemic inflammatory challenge (lipopolysaccharide (LPS), 1 mg/kg) produced prolonged (7 days) deficits in the LDR task. These data suggest that LDR task is a valuable platform for evaluating disease-relevant deficits in pattern separation and offers potential for identifying novel therapies.