Prefrontal neuronal ensembles link prior knowledge with novel actions during flexible action selection.

We make decisions based on currently perceivable information or an internal model of the environment. The medial prefrontal cortex (mPFC) and its interaction with the hippocampus have been implicated in the latter, model-based decision-making; however, the underlying computational properties remain incompletely understood. We have examined mPFC spiking and hippocampal oscillatory activity while rats flexibly select new actions using a known associative structure of environmental cues and outcomes. During action selection, the mPFC reinstates representations of the associative structure. These awake reactivation events are accompanied by synchronous firings among neurons coding the associative structure and those coding actions. Moreover, their functional coupling is strengthened upon the reactivation events leading to adaptive actions. In contrast, only cue-coding neurons improve functional coupling during hippocampal sharp wave ripples. Thus, the lack of direct experience disconnects the mPFC from the hippocampus to independently form self-organized neuronal ensemble dynamics linking prior knowledge with novel actions.

Lateral Entorhinal Cortex Suppresses Drift in Cortical Memory Representations.

Memory retrieval is thought to depend on the reinstatement of cortical memory representations guided by pattern completion processes in the hippocampus. The lateral entorhinal cortex (LEC) is one of the intermediary regions supporting hippocampal-cortical interactions and houses neurons that prospectively signal past events in a familiar environment. To investigate the functional relevance of the activity of the LEC for cortical reinstatement, we pharmacologically inhibited the LEC and examined its impact on the stability of ensemble firing patterns in one of the efferent targets of the LEC, the medial prefrontal cortex (mPFC). When male rats underwent multiple epochs of identical stimulus sequences in the same environment, the mPFC maintained a stable ensemble firing pattern across repetitions, particularly when the sequence included pairings of neutral and aversive stimuli. With LEC inhibition, the mPFC still formed an ensemble pattern that accurately captured stimuli and their associations within each epoch. However, LEC inhibition markedly disrupted its consistency across the epochs by decreasing the proportion of mPFC neurons that stably maintained firing selectivity for stimulus associations. Thus, the LEC stabilizes cortical representations of learned stimulus associations, thereby facilitating the recovery of the original memory trace without generating a new, redundant trace for familiar experiences. Failure of this process might underlie retrieval deficits in conditions associated with degeneration of the LEC, such as normal aging and Alzheimer's disease.SIGNIFICANCE STATEMENT To recall past events, the brain needs to reactivate the activity patterns that occurred during those events. However, such reinstatement of memory traces is not trivial because it goes against the natural tendency of the brain to restructure the activity patterns continuously. We found that dysfunction of a brain region called the LEC worsened the drift of the brain activity when rats repeatedly underwent the same events in the same room and made them behave as if they had never experienced these events before. Thus, the LEC stabilizes the brain activity to facilitate the recovery of the original memory trace. Failure of this process might underlie memory problems in elderly and Alzheimer's disease patients with the degenerated LEC.

Prefrontal Neural Ensembles Develop Selective Code for Stimulus Associations within Minutes of Novel Experiences.

Prevailing theories posit that the hippocampus rapidly learns stimulus conjunctions during novel experiences, whereas the neocortex learns slowly through subsequent, off-line interaction with the hippocampus. Parallel evidence, however, shows that the medial prefrontal cortex (mPFC; a critical node of the neocortical network supporting long-term memory storage) undergoes rapid modifications of gene expression, synaptic structure, and physiology at the time of encoding. These observations, along with impaired learning with disrupted mPFC, suggest that mPFC neurons may exhibit rapid neural plasticity during novel experiences; however, direct empirical evidence is lacking. We extracellularly recorded action potentials of cells in the prelimbic region of the mPFC, while male rats received a sequence of stimulus presentations for the first time in life. Moment-to-moment tracking of neural ensemble firing patterns revealed that the prelimbic network activity exhibited an abrupt transition within 1 min after the first encounter of an aversive but not neutral stimulus. This network-level change was driven by ∼15% of neurons that immediately elevated their spontaneous firing rates (FRs) and developed firing responses to a neutral stimulus preceding the aversive stimulus within a few instances of their pairings. When a new sensory stimulus was paired with the same aversive stimulus, about half of these neurons generalized firing responses to the new stimulus association. Thus, prelimbic neurons are capable of rapidly forming ensemble codes for novel stimulus associations within minutes. This circuit property may enable the mPFC to rapidly detect and selectively encode the central content of novel experiences.SIGNIFICANCE STATEMENT During a new experience, a region of the brain, called the hippocampus, rapidly forms its memory and later instructs another region, called the neocortex, that stores its content. Consistent with this dominant view, cells in the neocortex gradually strengthen the selectivity for the memory content over weeks after novel experiences. However, we still do not know precisely when these cells begin to develop the selectivity. We found that neocortical cells were capable of forming the selectivity for ongoing events within a few minutes of new experiences. This finding provides support for an alternative view that the neocortex works with, but not follows, the hippocampus to form new memories.

Neural representations of time-linked memory.

Many cognitive processes, such as episodic memory and decision making, rely on the ability to form associations between two events that occur separately in time. The formation of such temporal associations depends on neural representations of three types of information: what has been presented (trace holding), what will follow (temporal expectation), and when the following event will occur (explicit timing). The present review seeks to link these representations with firing patterns of single neurons recorded while rodents and non-human primates associate stimuli, outcomes, and motor responses over time intervals. Across these studies, two distinct firing patterns were observed in the hippocampus, neocortex, and striatum: some neurons change firing rates during or shortly after the stimulus presentation and sustain the firing rate stably or sidlingly during the subsequent intervals (tonic firings). Other neurons transiently change firing rates during a specific moment within the time intervals (phasic firings), and as a group, they form a sequential firing pattern that covers the entire interval. Clever task designs used in some of these studies collectively provide evidence that both tonic and phasic firing responses represent trace holding, temporal expectation, and explicit timing. Subsequently, we applied machine-learning based classification approaches to the two firing patterns within the same dataset collected from rat medial prefrontal cortex during trace eyeblink conditioning. This quantitative analysis revealed that phasic-firing patterns showed greater selectivity for stimulus identity and temporal position than tonic-firing patterns. Our summary illuminates distributed neural representations of temporal association in the forebrain and generates several ideas for future investigations.

Phasic and tonic neuron ensemble codes for stimulus-environment conjunctions in the lateral entorhinal cortex.

The lateral entorhinal cortex (LEC) is thought to bind sensory events with the environment where they took place. To compare the relative influence of transient events and temporally stable environmental stimuli on the firing of LEC cells, we recorded neuron spiking patterns in the region during blocks of a trace eyeblink conditioning paradigm performed in two environments and with different conditioning stimuli. Firing rates of some neurons were phasically selective for conditioned stimuli in a way that depended on which room the rat was in; nearly all neurons were tonically selective for environments in a way that depended on which stimuli had been presented in those environments. As rats moved from one environment to another, tonic neuron ensemble activity exhibited prospective information about the conditioned stimulus associated with the environment. Thus, the LEC formed phasic and tonic codes for event-environment associations, thereby accurately differentiating multiple experiences with overlapping features.

Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal-prefrontal coherence.

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (SCG) has been used to treat patients with treatment-resistant depression. As in humans, DBS applied to the ventromedial prefrontal cortex of rats induces antidepressant-like responses. Physiological interactions between structures that play a role in depression and antidepressant treatment are still unknown. The present study examined the effect of DBS on inter-region communication by measuring the coherence of local field potentials in the rat infralimbic cortex (IL; homologue of the SCG) and one of its major afferents, the ventral hippocampus (VH). Rats received daily IL DBS treatment (100 µA, 90 µs, 130 Hz; 8h/day). Recordings were conducted in unrestrained, behaving animals on the day before treatment, after 1 and 10 days of treatment, and 10 days stimulation offset. VH-IL coherence in the 2-4 Hz range was reduced in DBS-treated animals compared with shams after 10 days, but not after only 1 day of treatment. No effect of DBS was observed in the 6-10 Hz (theta) range, where coherence was generally high and could be further evoked with a loud auditory stimulus. Finally, coherence was not affected by fluoxetine (10mg/kg), suggesting that the effects of DBS were not likely mediated by increased serotonin levels. While these data support the hypothesis that DBS disrupts communication between regions important for expectation-based control of emotion, they also suggest that lasting physiological effects require many days of treatment and, furthermore, may be specific to lower-frequency patterns, the nature and scope of which await further investigation.

Are valence and arousal separable in emotional experience?

The bipolar valence-arousal model of conscious experience of emotions is prominent in emotion research. In this work, we examine the validity of this model in the context of feelings elicited by visual stimuli. In particular, we examine whether arousal has a unique contribution over bivariate valence (separate measures for pleasure and displeasure) in explaining physiological arousal (electrodermal activity, EDA) and self-reported feelings at the level of item-specific responses across and within individuals. Our results suggest that self-reports of arousal have neither an advantage in predicting EDA nor make a unique contribution when valence is present in the model. Acceptance of the null hypothesis was confirmed with the use of the Bayesian information criterion. Arousal also showed no advantage over valence in predicting global feelings, but demonstrated a small unique component (1.5% to 4% of variance explained). These results have practical implications for both experimental design in the study of emotions and the underlying bases of their conscious experience.

Spending one's time: the hedonic principle in ad libitum viewing of pictures.

The hedonic principle maintains that humans strive to maximize pleasant feelings and avoid unpleasant feelings. Surprisingly, and contrary to hedonic logic, previous experiments have demonstrated a relationship between picture viewing time and arousal (activation) but not with valence (pleasure vs. displeasure), suggesting that arousal rather than the hedonic principle accounts for how individuals choose to spend their time. In 2 experiments we investigated the arousal and hedonic principles underlying viewing time behavior while controlling for familiarity with stimuli, picture complexity, and demand characteristics. Under ad libitum conditions of picture viewing, we found strong relationships between viewing time, valence, and facial corrugator electomyographic (EMG) activity with familiar but not novel pictures. Viewing time of novel stimuli was largely associated with arousal and visual complexity. We conclude that only after initial information about the stimulus is gathered, where we choose to spend our time is guided by the hedonic principle.