Aaron J. Gruber

The role of medial prefrontal cortex in memory and decision making.

Some have claimed that the medial prefrontal cortex (mPFC) mediates decision making. Others suggest mPFC is selectively involved in the retrieval of remote long-term memory. Yet others suggests mPFC supports memory and consolidation on time scales ranging from seconds to days. How can all these roles be reconciled? We propose that the function of the mPFC is to learn associations between context, locations, events, and corresponding adaptive responses, particularly emotional responses. Thus, the ubiquitous involvement of mPFC in both memory and decision making may be due to the fact that almost all such tasks entail the ability to recall the best action or emotional response to specific events in a particular place and time. An interaction between multiple memory systems may explain the changing importance of mPFC to different types of memories over time. In particular, mPFC likely relies on the hippocampus to support rapid learning and memory consolidation.

Dopamine modulation in the basal ganglia locks the gate to working memory

The prefrontal cortex and basal ganglia are deeply implicated in working memory. Both structures are subject to dopaminergic neuromodulation in a way that exerts a critical influence on the proper operation of working memory. We present a novel network model to elucidate the role of phasic dopamine in the interaction of these two structures in initiating and maintaining mnemonic activity. We argue that neuromodulation plays a critical role in protecting memories against both internal and external sources of noise. Increases in cortical gain engendered by prefrontal dopamine release help make memories robust against external distraction, but do not offer protection against internal noise accompanying recurrent cortical activity. Rather, the output of the basal ganglia provides the gating function of stabilization against noise and distraction by enhancing select memories through targeted disinhibition of cortex. Dopamine in the basal ganglia effectively locks this gate by influencing the stability of up and down states in the striatum. Dopamine’s involvement in affective processing endows this gating with specificity to motivational salience. We model a spatial working memory task and show that these combined effects of dopamine lead to superior performance.

Orbitofrontal Cortex Supports Behavior and Learning Using Inferred But Not Cached Values

Experience Versus Models There is an ongoing debate over what the orbitofrontal cortex contributes to behavior, learning, and decision-making. Jones et al. (p. 953) found that the orbitofrontal cortex was important for value-based computations when value must be inferred from an associative model of the task but not when value estimates based on previous experience are sufficient. This result calls into question the assumption that this region simply signals economic value. However, it would be consistent with a concept of the orbitofrontal cortex as being important for constructing model-based representations of the world that are orthogonal to value. Inferred value can be used to both guide behavior and modulate learning in rats. Computational and learning theory models propose that behavioral control reflects value that is both cached (computed and stored during previous experience) and inferred (estimated on the fly on the basis of knowledge of the causal structure of the environment). The latter is thought to depend on the orbitofrontal cortex. Yet some accounts propose that the orbitofrontal cortex contributes to behavior by signaling “economic” value, regardless of the associative basis of the information. We found that the orbitofrontal cortex is critical for both value-based behavior and learning when value must be inferred but not when a cached value is sufficient. The orbitofrontal cortex is thus fundamental for accessing model-based representations of the environment to compute value rather than for signaling value per se.

More is less: a disinhibited prefrontal cortex impairs cognitive flexibility

The prefrontal cortex (PFC) is critical for decision making, and it becomes dysfunctional in many neuropsychiatric disorders. Studies in schizophrenia patients and relevant animal models suggest loss of PFC inhibitory interneuron function. For instance, rats with a neonatal ventral hippocampal lesion (NVHL) show a deficient modulation of PFC interneurons by dopamine (DA). Whether the PFC becomes disinhibited in this model and alters decision making remains to be determined. Here, we recorded neural activity in the medial PFC of NVHL rats during a reward-discounting choice task that activated DA systems. Rats were trained to sample odors that instructed them to select one of two feeders that delivered unequal amounts of liquid. Putative pyramidal neurons in the PFC were hyperactive whereas task-related field potential oscillations were significantly reduced in NVHL rats, consistent with impaired interneuron activation by DA during odor sampling leading to disorganized processing. Cognitive flexibility was tested by examining response bias and errors after reversing reward outcomes. NVHL rats demonstrated impaired flexibility as they were less able to track changes in reward outcome and made more response errors than controls did. Reducing cortical excitability with the metabotropic glutamate receptor 2/3 agonist LY379268 (1 mg/kg, i.p.) improved behavioral flexibility in NVHL rats but not controls. Furthermore, D2 dopamine receptors were involved, as the antagonist eticlopride (0.02 mg/kg, i.p.) reduced the ability to switch only in control animals. We conclude that NVHL rats present PFC disinhibition, which affects neural information processing and the selection of appropriate behavioral responses.

Context, emotion, and the strategic pursuit of goals: interactions among multiple brain systems controlling motivated behavior

Motivated behavior exhibits properties that change with experience and partially dissociate among a number of brain structures. Here, we review evidence from rodent experiments demonstrating that multiple brain systems acquire information in parallel and either cooperate or compete for behavioral control. We propose a conceptual model of systems interaction wherein a ventral emotional memory network involving ventral striatum (VS), amygdala, ventral hippocampus, and ventromedial prefrontal cortex triages behavioral responding to stimuli according to their associated affective outcomes. This system engages autonomic and postural responding (avoiding, ignoring, approaching) in accordance with associated stimulus valence (negative, neutral, positive), but does not engage particular operant responses. Rather, this emotional system suppresses or invigorates actions that are selected through competition between goal-directed control involving dorsomedial striatum (DMS) and habitual control involving dorsolateral striatum (DLS). The hippocampus provides contextual specificity to the emotional system, and provides an information rich input to the goal-directed system for navigation and discriminations involving ambiguous contexts, complex sensory configurations, or temporal ordering. The rapid acquisition and high capacity for episodic associations in the emotional system may unburden the more complex goal-directed system and reduce interference in the habit system from processing contingencies of neutral stimuli. Interactions among these systems likely involve inhibitory mechanisms and neuromodulation in the striatum to form a dominant response strategy. Innate traits, training methods, and task demands contribute to the nature of these interactions, which can include incidental learning in non-dominant systems. Addition of these features to reinforcement learning models of decision-making may better align theoretical predictions with behavioral and neural correlates in animals.

The nucleus accumbens: a switchboard for goal-directed behaviors.

Reward intake optimization requires a balance between exploiting known sources of rewards and exploring for new sources. The prefrontal cortex (PFC) and associated basal ganglia circuits are likely candidates as neural structures responsible for such balance, while the hippocampus may be responsible for spatial/contextual information. Although studies have assessed interactions between hippocampus and PFC, and between hippocampus and the nucleus accumbens (NA), it is not known whether 3-way interactions among these structures vary under different behavioral conditions. Here, we investigated these interactions with multichannel recordings while rats explored an operant chamber and while they performed a learned lever-pressing task for reward in the same chamber shortly afterward. Neural firing and local field potentials in the NA core synchronized with hippocampal activity during spatial exploration, but during lever pressing they instead synchronized more strongly with the PFC. The latter is likely due to transient drive of NA neurons by bursting prefrontal activation, as in vivo intracellular recordings in anesthetized rats revealed that NA up states can transiently synchronize with spontaneous PFC activity and PFC stimulation with a bursting pattern reliably evoked up states in NA neurons. Thus, the ability to switch synchronization in a task-dependent manner indicates that the NA core can dynamically select its inputs to suit environmental demands, thereby contributing to decision-making, a function that was thought to primarily depend on the PFC.

Formation and Reverberation of Sequential Neural Activity Patterns Evoked by Sensory Stimulation Are Enhanced during Cortical Desynchronization

Memory formation is hypothesized to involve the generation of event-specific neural activity patterns during learning and the subsequent spontaneous reactivation of these patterns. Here, we present evidence that these processes can also be observed in urethane-anesthetized rats and are enhanced by desynchronized brain state evoked by tail pinch, subcortical carbachol infusion, or systemic amphetamine administration. During desynchronization, we found that repeated tactile or auditory stimulation evoked unique sequential patterns of neural firing in somatosensory and auditory cortex and that these patterns then reoccurred during subsequent spontaneous activity, similar to what we have observed in awake animals. Furthermore, the formation of these patterns was blocked by an NMDA receptor antagonist, suggesting that the phenomenon depends on synaptic plasticity. These results suggest that anesthetized animals with a desynchronized brain state could serve as a convenient model for studying stimulus-induced plasticity to improve our understanding of memory formation and replay in the brain.

Cortically Activated Interneurons Shape Spatial Aspects of Cortico-Accumbens Processing

Basal ganglia circuits are organized as parallel loops that have been proposed to compete in a winner-take-all fashion to determine the appropriate behavioral outcome. However, limited experimental support for strong lateral inhibition mechanisms within striatal regions questions this model. Here, stimulation of the prefrontal cortex (PFC) using naturally occurring bursty patterns inhibited firing in most nucleus accumbens (NA) projection neurons. When an excitatory response was observed for one stimulation site, neighboring PFC sites evoked inhibition in the same neuron. Furthermore, PFC stimulation activated interneurons, and PFC-evoked inhibition was blocked by GABA(A) antagonists in corticoaccumbens slice preparations. Thus bursting PFC activity recruits local inhibition in the NA, shaping responses of projection neurons with a topographical arrangement that allows inhibition among parallel corticoaccumbens channels. The data indicate a high order of information processing within striatal circuits that should be considered in models of basal ganglia function and disease.

Acute NMDA receptor antagonism disrupts synchronization of action potential firing in rat prefrontal cortex.

Antagonists of N-methyl-D-aspartate receptors (NMDAR) have psychotomimetic effects in humans and are used to model schizophrenia in animals. We used high-density electrophysiological recordings to assess the effects of acute systemic injection of an NMDAR antagonist (MK-801) on ensemble neural processing in the medial prefrontal cortex of freely moving rats. Although MK-801 increased neuron firing rates and the amplitude of gamma-frequency oscillations in field potentials, the synchronization of action potential firing decreased and spike trains became more Poisson-like. This disorganization of action potential firing following MK-801 administration is consistent with changes in simulated cortical networks as the functional connections among pyramidal neurons become less clustered. Such loss of functional heterogeneity of the cortical microcircuit may disrupt information processing dependent on spike timing or the activation of discrete cortical neural ensembles, and thereby contribute to hallucinations and other features of psychosis induced by NMDAR antagonists.

Bursting Activation of Prefrontal Cortex Drives Sustained Up States in Nucleus Accumbens Spiny Neurons In Vivo

Hippocampal inputs to the nucleus accumbens (NA) have been proposed to implement a gating mechanism by driving NA medium spiny neurons (MSNs) to depolarized up states that facilitate action potential firing in response to brief activation of the prefrontal cortex (PFC). Brief PFC stimulation alone, on the other hand, could not drive NA up states. As these studies were conducted using single‐pulse PFC stimulation, it remains possible that PFC activation with naturalistic, bursty patterns can also drive up states in NA MSNs. Here, we assessed NA responses to PFC stimulation with a pattern similar to what is typically observed in awake animals during PFC‐relevant behaviors. In vivo intracellular recordings from NA MSNs revealed that brief 20–50 Hz PFC stimulus trains evoked depolarizations that were similar to spontaneous up states in NA MSNs and were sustained beyond stimulus offset. Similar train stimulation of corticoaccumbens afferents in a parasagittal slice preparation evoked large amplitude depolarizations in NA MSNs that were sustained during stimulation but decayed rapidly following stimulation offset, suggesting that activation of cortical afferents can drive MSN depolarizations but other mechanisms may contribute to sustaining up states. These data suggest that NA MSNs integrate temporal features of PFC activation and that the NA gating model can be reformulated to include a PFC‐driven gating mechanism during periods of high PFC firing, such as during cognitively demanding tasks. Synapse 63:173–180, 2009.