Perineuronal nets are associated with decision making under conditions of uncertainty in female but not male mice.

Biological sex influences decision-making processes in significant ways, differentiating the responses animals choose when faced with a range of stimuli. The neurobiological underpinnings that dictate sex differences in decision-making tasks remains an important open question, yet single-sex studies of males form most studies in behavioural neuroscience. Here we used female and male BALB/c mice on two spatial learning and memory tasks and examined the expression of perineuronal nets (PNNs) and parvalbumin interneurons (PV) in regions correlated with spatial memory. Mice underwent the aversive active place avoidance (APA) task or the appetitive trial-unique nonmatching-to-location (TUNL) touchscreen task. Mice in the APA cohort learnt to avoid the foot-shock and no differences were observed on key measures of the task nor in the number and intensity of PNNs and PV. On the delay but not separation manipulation in the TUNL task, females received more incorrect trials and less correct trials compared to males. Furthermore, females in this cohort exhibited higher intensity PNNs and PV cells in the agranular and granular retrosplenial cortex, compared to males. These data show that female and male mice perform similarly on spatial learning tasks. However, sex differences in neural circuitry may underly differences in making decisions under conditions of uncertainty on an appetitive task. These data emphasise the importance of using mice of both sexes in studies of decision-making neuroscience.

Activity in the Dorsomedial Striatum Underlies Serial Reversal Learning Performance Under Probabilistic Uncertainty.

Background: Corticostriatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in individuals with psychosis as well as their psychotic symptoms, suggesting that they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity. Methods: We used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway-specific corticostriatal activation. To determine the causal role of DMS activity, we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies. Results: Mice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency. Conclusions: Our work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine levels in the DMS could contribute to decision-making impairments in individuals with psychosis.

Activating the dorsomedial and ventral midbrain projections to the striatum differentially impairs goal-directed action in male mice.

The cognitive symptoms of schizophrenia are wide ranging and include impaired goal-directed action. This could be driven by an increase in dopamine transmission in the dorsomedial striatum, a pathophysiological hallmark of schizophrenia. Although commonly associated with psychotic symptoms, dopamine signalling in this region also modulates associative learning that aids in the execution of actions. To gain a better understanding of the role of subcortical dopamine in learning and decision-making, we assessed goal-directed action in male mice using the cross-species outcome-specific devaluation task (ODT). First, we administered systemic amphetamine during training to determine the impact of altered dopaminergic signaling on associative learning. Second, we used pathway-specific chemogenetic approaches to activate the dorsomedial and ventral striatal pathways (that originate in the midbrain) to separately assess learning and performance. Amphetamine treatment during learning led to a dose-dependent impairment in goal-directed action. Activation of both striatal pathways during learning also impaired performance. However, when these pathways were activated during choice, only activation of the ventral pathway impaired goal-directed action. This suggests that elevated transmission in the dorsomedial striatal pathway impairs associative learning processes that guide the goal-directed execution of actions. By contrast, elevated transmission of the ventral striatal pathway disrupts the encoding of outcome values that are important for both associative learning and choice performance. These findings highlight the differential roles of the dorsomedial and ventral inputs into the striatum in goal-directed action and provides insight into how striatal dopamine signaling may contribute to the cognitive problems in those with schizophrenia.