Flexible versus Fixed Spatial Self-Ordered Response Sequencing: Effects of Inactivation and Neurochemical Modulation of Ventrolateral Prefrontal Cortex.

Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D2 and 5-HT2A-receptor (R) blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed two and three response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5-HT2A-R blockade, with the former producing error perseveration on incorrect trials, though not significantly impairing accuracy overall, and the latter significantly impairing accuracy but not error perseveration. A second cohort of marmosets were directly compared on performance of fixed versus variable spatial arrays. Inactivation of vlPFC again impaired self-ordered sequencing, but only with varying, and not fixed spatial arrays, the latter leading to the consistent use of fewer, preferred sequences. These findings add to evidence that vlPFC is implicated in goal-directed behavior that requires higher-order response heuristics that can be applied flexibly over different (variable), as compared with fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance.SIGNIFICANCE STATEMENT This investigation employing local intracerebral infusions to inactivate the lateral prefrontal cortex (PFC) of the New World marmoset reveals the important role of this region in self-ordered response sequencing in variable but not fixed spatial arrays. These novel findings emphasize the higher order functions of this region, contributing to cognitive flexibility and planning of goal directed behavior. The investigation also reports for the first time somewhat contrasting neuromodulatory deficits produced by infusions of dopamine (DA) D2 and 5-HT2A receptor (R) antagonists into the same region, of possible significance for understanding cognitive deficits produced by anti-psychotic drugs.

The role of rat dorsomedial prefrontal cortex in spatial working memory.

We used an operant delayed spatial alternation task to examine the role of rat dorsomedial prefrontal cortex (dmPFC) in spatial working memory. The task was designed to restrict movements during the delay period to minimize use of motor-mediating strategies. Inactivation of dmPFC (muscimol) resulted in increased errors and increased the temporal variability of responding. Animals did not show perseveration after errors (i.e., responding again at the erroneous location). Under control conditions, the time between spatial responses was greater and more variable before errors as compared to correct responses. These effects were eliminated when muscimol was infused into dmPFC. Trial outcome also affected movement and delay times in the next trial. This effect was diminished with muscimol in dmPFC. By contrast, when muscimol was infused in dorsal agranular insular cortex (AId)-a region that is strongly interconnected with dorsomedial prefrontal regions-there was no effect on delayed spatial alternation performance. These experiments confirm that dmPFC is necessary for successful delayed spatial alternation and establish that there is a relationship between response time variability and trial outcome that depends on dorsomedial prefrontal function.

Reversible inactivations of rat medial prefrontal cortex impair the ability to wait for a stimulus.

In simple reaction time tasks, lesions of rat dorsomedial prefrontal cortex impair the ability to wait for trigger stimuli and result in increased premature responding. This effect could be due to impairments in attending to trigger stimuli, estimating the timing of trigger stimuli, or inhibitory control of the motor response. Here, we examined these issues by reversibly inactivating dorsomedial prefrontal cortex during simple reaction time tasks with variable or fixed foreperiods. There were three consistent effects of dorsomedial prefrontal cortex inactivation: 1) increased premature responding, 2) increased variability in the timing of premature responses, and 3) speeded response latencies, especially on trials with short foreperiods in tasks with variable foreperiods. We observed these effects independent of differences in foreperiod duration, foreperiod variability, and stimulus probabilities. Therefore, dorsomedial prefrontal cortex appears not to be involved in attending to the trigger stimulus or in time estimation. Instead, we suggest that dorsomedial prefrontal cortex is critical for inhibiting responses before the maximum foreperiod duration, i.e. the "deadline" [Ollman RT, Billington MJ (1972) The deadline model for simple reaction times. Cognit Psychol 3:311-336], after which the rat should respond even if the trigger stimulus has not occurred.