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

Abstract

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 D 2 and 5-HT 2A receptor 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 2 and 3 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 D 2 and 5HT 2A receptor 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 to fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance.

A direct excitatory projection from entorhinal layer 6b neurons to the hippocampus contributes to spatial coding and memory

“…Although motor or sensory deficits can be ruled out, because they would result in a location-independent decrease in behavioral performance, more complex network effects beyond the EC cannot be excluded. These could arise from alterations to activity in the prefrontal cortex, which was previously shown to be involved in spatial tasks requiring cognitive flexibility 65 , 66 (but also see ref. 67 ).…”

A Multi-task Platform for Profiling Cognitive and Motivational Constructs in Humans and Nonhuman Primates

“…Humans with schizophrenia show impairments of spatial learning (Bakker et al, 2020), error monitoring (number of rule-breaking errors), efficiency (time and number of moves to completion), and show perseverations (Snyder et al, 2008) which can improve with dopaminergic and cholinergic drugs (Lieberman et al, 2013; Pietrzak et al, 2009; Pietrzak et al, 2010). Maze learning also involves the recall of spatial sequences, which involves the hippocampus (Buzsaki & Tingley, 2018), ventrolateral prefrontal cortex (Axelsson et al, 2021) and the dorsolateral prefrontal cortex (Mushiake et al, 2006; Saito et al, 2005). It shares similarities to the path learning of nonhuman primates controlling cursors (Mushiake et al, 2001), and spatial relational learning of rodents in the Morris Water Maze, which is linked to the hippocampal system and to cholinergic modulation as muscarinic compounds reverse deficits in spatial learning and memory (Popiolek et al, 2019).…”

“…The CR task has the same requirements as the Delayed Recognition Span task that depends on prefrontal cortex and its dopaminergic and noradrenergic functioning (Moore et al, 2005). It requires self-ordered search for a new target, which has been associated specifically with the ventral and lateral prefrontal cortex, but not the orbitofrontal or parietal cortex (Axelsson et al, 2021; Champod & Petrides, 2007; Walker et al, 2009), and in humans is causally supported by the inferior frontal gyrus (Chase et al, 2008). Deficits in self-ordered selection tasks are evident in humans diagnosed with attention-deficit-hyperactivity disorder (ADHD) (Dowson et al, 2004; Fried et al, 2015) and schizophrenia (Badcock et al, 2005; Pantelis et al, 1999), including first degree relatives and monozygotic twins of schizophrenic patients (Pirkola et al, 2005; Wood et al, 2003) even when they have no altered cognitive functioning (Joyce et al, 2005).…”

Comparative roles of caudate and putamen in the serial order of behavior: Effects of striatal glutamate receptor blockade on variable versus fixed spatial self-ordered sequencing in marmosets

“…Previously, we have shown that the contribution of vlPFC in marmosets to self-ordered response sequencing of spatial arrays is limited to when the arrays vary across trials, requiring flexible, goal-directed behavior for successful performance (Axelsson et al, 2021). In contrast, when the same spatial array was used across trials in a fixed version of the self-ordered sequencing task which encouraged more automated responding involving use of a restricted set of preferred response sequences, inactivation of the vlPFC was without effect (Axelsson et al, 2021).…”

“…In the marmoset monkey, fiber-sparing lesions to the combined lateral, orbital, and anteroventral regions of the PFC confirmed its role in self-ordered sequencing (Collins et al, 1998). Subsequently, this effect was localized to ventrolateral (vl)PFC, but not orbitofrontal cortex (Axelsson et al, 2021; Walker et al, 2009).…”