Deliberative Behaviors and Prefrontal-Hippocampal Coupling are Disrupted in a Rat Model of Fetal Alcohol Spectrum Disorders.

Fetal alcohol spectrum disorders (FASDs) are characterized by a range of physical, cognitive, and behavioral impairments. Determining how temporally specific alcohol exposure (AE) affects neural circuits is crucial to understanding the FASD phenotype. Third trimester AE can be modeled in rats by administering alcohol during the first two postnatal weeks, which damages the medial prefrontal cortex (mPFC), thalamic nucleus reuniens, and hippocampus (HPC), structures whose functional interactions are required for working memory and executive function. Therefore, we hypothesized that AE during this period would impair working memory, disrupt choice behaviors, and alter mPFC-HPC oscillatory synchrony. To test this hypothesis, we recorded local field potentials from the mPFC and dorsal HPC as AE and sham intubated (SI) rats performed a spatial working memory task in adulthood and implemented algorithms to detect vicarious trial and errors (VTEs), behaviors associated with deliberative decision-making. We found that, compared to the SI group, the AE group performed fewer VTEs and demonstrated a disturbed relationship between VTEs and choice outcomes, while spatial working memory was unimpaired. This behavioral disruption was accompanied by alterations to mPFC and HPC oscillatory activity in the theta and beta bands, respectively, and a reduced prevalence of mPFC-HPC synchronous events. When trained on multiple behavioral variables, a machine learning algorithm could accurately predict whether rats were in the AE or SI group, thus characterizing a potential phenotype following third trimester AE. Together, these findings indicate that third trimester AE disrupts mPFC-HPC oscillatory interactions and choice behaviors.

Using synchronized brain rhythms to bias memory-guided decisions.

Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6-11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain-machine interface that initiated task trials based on the magnitude of prefrontal-hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain-machine interfacing.

Pausing and reorienting behaviors enhance the performance of a spatial working memory task.

During spatial working memory tasks, animals need to retain information about a previous trial in order to successfully select their next trajectory. Specifically, the delayed non-match to position task requires rats to follow a cued sample trajectory, then select the opposite route after a delay period. When faced with this choice, rats will occasionally exhibit complex behaviors, such as pausing and sweeping their head back and forth. These behaviors, called vicarious trial and error (VTE), are thought to be a behavioral manifestation of deliberation. However, we identified similarly complex behaviors during sample-phase traversals, despite the fact that these laps do not require a decision. First, we identified that these behaviors occurred more often after incorrect trials than before them, indicating that rats are retaining information between trials. Next, we determined that these pause-and-reorient (PAR) behaviors increased the likelihood of the next choice being selected correctly, suggesting that these behaviors assist the rat in successful task performance. Finally, we identified similarities between PARs and choice-phase VTEs, suggesting that VTEs may not only be reflective of deliberation, but may also contribute to a strategy for successful performance of spatial working memory tasks.

The ventral midline thalamus coordinates prefrontal-hippocampal neural synchrony during vicarious trial and error.

When faced with difficult choices, the possible outcomes are considered through a process known as deliberation. In rats, deliberation is thought to be reflected by pause-and-reorienting behaviors, better known as vicarious trial and errors (VTEs). While VTEs are thought to require medial prefrontal cortex (mPFC) and dorsal hippocampal (dHPC) interactions, no empirical evidence has yet demonstrated such a dual requirement. The nucleus reuniens (Re) of the ventral midline thalamus is anatomically connected with both the mPFC and dHPC, is required for HPC-dependent spatial memory tasks, and is critical for mPFC-dHPC neural synchronization. Currently, it is unclear if, or how, the Re is involved in deliberation. Therefore, by examining the role of the Re on VTE behaviors, we can better understand the anatomical and physiological mechanisms supporting deliberation. Here, we examined the impact of Re suppression on VTE behaviors and mPFC-dHPC theta synchrony during asymptotic performance of a HPC-dependent delayed alternation (DA) task. Pharmacological suppression of the Re increased VTE behaviors that occurred with repetitive choice errors. These errors were best characterized as perseverative behaviors, in which some rats repeatedly selected a goal arm that previously yielded no reward. We then examined the impact of Re suppression on mPFC-dHPC theta synchrony during VTEs. We found that during VTEs, Re inactivation was associated with a reduction in mPFC-dHPC theta coherence and mPFC-to-dHPC theta directionality. Our findings suggest that the Re contributes to deliberation by coordinating mPFC-dHPC neural interactions.

Representations of On-Going Behavior and Future Actions During a Spatial Working Memory Task by a High Firing-Rate Population of Medial Prefrontal Cortex Neurons.

Spatial working memory (SWM) requires the encoding, maintenance, and retrieval of spatially relevant information to guide decision-making. The medial prefrontal cortex (mPFC) has long been implicated in the ability of rodents to perform SWM tasks. While past studies have demonstrated that mPFC ensembles reflect past and future experiences, most findings are derived from tasks that have an experimental overlap between the encoding and retrieval of trajectory specific information. In this study, we recorded single units from the mPFC of rats as they performed a T-maze delayed non-match to position (DNMP) task. This task consists of an encoding dominant sample phase, a memory maintenance delay period, and retrieval dominant choice phase. Using a linear classifier, we investigated whether distinct ensembles collectively reflect various trajectory-dependent experiences. We find that a population of high-firing rate mPFC neurons both predict a future choice and reflect changes in trajectory-dependent behaviors. We then developed a modeling procedure that estimated the number of high and low-firing rate units required to dissociate between various experiences. We find that low firing rate ensembles weakly reflect the direction that rats were forced to turn on the sample phase. This was in contrast to the highly active population that could effectively predict both future decision-making on early stem traversals and trajectory-divergences at T-junction. Finally, we compared the ensemble size necessary to code a forced trajectory to the size required to predict a decision. We provide evidence to suggest that a larger number of highly active neurons are employed during decision-making processes when compared to rewarded forced behaviors. Together, our study provides important insight into how specific ensembles of mPFC units support upcoming choices and ongoing behavior during SWM.