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Anterior cingulate cortex (ACC) activity is important for operations that require the ability to integrate multiple experiences over time, such as rule learning, cognitive flexibility, working memory, and long-term memory recall. To shed light on this, we analyzed neuronal activity while rats repeated the same behaviors during hour-long sessions to investigate how activity changed over time. We recorded neuronal ensembles as rats performed a decision-free operant task with varying reward likelihoods at three different response ports (n = 5). Neuronal state space analysis revealed that each repetition of a behavior was distinct, with more recent behaviors more similar than those further apart in time. ACC activity was dominated by a slow, gradual change in low-dimensional representations of neural state space aligning with the pace of behavior. Temporal progression, or drift, was apparent on the top principal component for every session and was driven by the accumulation of experiences and not an internal clock. Notably, these signals were consistent across subjects, allowing us to accurately predict trial numbers based on a model trained on data from a different animal. We observed that non-continuous ramping firing rates over extended durations (tens of minutes) drove the low-dimensional ensemble representations. 40% of ACC neurons' firing ramped over a range of trial lengths and combinations of shorter duration ramping neurons created ensembles that tracked longer durations. These findings provide valuable insights into how the ACC, at an ensemble level, conveys temporal information by reflecting the accumulation of experiences over extended periods., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cognitive control involves allocating cognitive effort according to internal needs and task demands and the Anterior Cingulate Cortex (ACC) is hypothesized to play a central role in this process. We investigated the neural basis of cognitive control in the ACC of rats performing an adjusting-amount delay discounting task. Decision-making in this this task can be guided by using either a lever-value tracking strategy, requiring a 'resource-based' form of cognitive effort or a lever-biased strategy requiring a 'resistance-based' form of cognitive effort. We found that ACC ensembles always tightly tracked lever value on each trial, indicative of a resource-based control signal. These signals were prevalent in the neural recordings and were influenced by the delay. A shorter delay was associated with devaluing of the immediate option and a longer delay was associated with overvaluing of the immediate option. In addition, ACC theta (6-12Hz) oscillations were observed at the choice point of rats exhibiting a resistance-based strategy. These data provide candidates of neural activity patterns in the ACC that underlie the use of 'resource-based' and 'resistance-based' cognitive effort. Furthermore, these data illustrate how strategies can be engaged under different conditions in individual subjects., Competing Interests: COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.

Behaviors and their execution depend on the context and emotional state in which they are performed. The contextual modulation of behavior likely relies on regions such as the anterior cingulate cortex (ACC) that multiplex information about emotional/autonomic states and behaviors. The objective of the present study was to understand how the representations of behaviors by ACC neurons become modified when performed in different emotional states. A pipeline of machine learning techniques was developed to categorize and classify complex, spontaneous behaviors in male rats from the video. This pipeline, termed Hierarchical Unsupervised Behavioural Discovery Tool (HUB-DT), discovered a range of statistically separable behaviors during a task in which motivationally significant outcomes were delivered in blocks of trials that created three unique "emotional contexts." HUB-DT was capable of detecting behaviors specific to each emotional context and was able to identify and segregate the portions of a neural signal related to a behavior and to emotional context. Overall, ∼10× as many neurons responded to behaviors in a contextually dependent versus a fixed manner, highlighting the extreme impact of emotional state on representations of behaviors that were precisely defined based on detailed analyses of limb kinematics. This type of modulation may be a key mechanism that allows the ACC to modify the behavioral output based on emotional states and contextual demands., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Dopamine (DA) signalling in the nucleus accumbens (NAc) motivates behavior in part by adjusting the exerted effort according to the anticipated value of the outcome. Here we examined the effects of optogenetic activation or inhibition of the glutamatergic ventral subiculum (vSub) to NAc pathway on motivation to work for food rewards and locomotor behavior. Using a novel probe that combines optical stimulation with microdialysis, we show that channelrhodopsin2 (ChR2)-mediated activation of these glutamatergic afferents increased DA efflux in the NAc. This protocol also selectively influenced motivation to seek food in a progressive-ratio (PR) task by re-invigorating lever-pressing, but only during a period of reduced motivation following failure to achieve food reward (i.e., after the breakpoint, BP). Importantly, identical ChR2-mediated photostimulation parameters failed to affect the rate of operant responding in the PR segment prior to reaching the BP. In contrast, during the segment of vigorous lever-pressing prior to the BP, halorhodopsin-mediated optogenetic inhibition of glutamatergic vSub-NAc activity caused an immediate and sustained suppression of food-seeking behavior. Based on these results, we conclude that glutamatergic vSub-NAc afferents can modulate food-seeking behavior, including 'response vigor', as a function of present motivational state. In a 'low-motivational state' following failure to achieve an anticipated reward, optogenetic stimulation of this pathway can reinvigorate lever-pressing behavior. In turn, inhibition of this glutamatergic pathway appears to decrease motivated responding. These data may be relevant to dysregulated motivational states common to psychiatric conditions, including depression, schizophrenia, and substance use disorders., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite being an intensive area of research, the function of the anterior cingulate cortex (ACC) remains somewhat of a mystery. Human imaging studies implicate the ACC in various cognitive functions, yet surgical ACC lesions used to treat emotional disorders have minimal lasting effects on cognition. An alternative view is that ACC regulates autonomic states, consistent with its interconnectivity with autonomic control regions and that stimulation evokes changes in autonomic/emotional states. At the cellular level, ACC neurons are highly multi-modal and promiscuous, and can represent a staggering array of task events. These neurons nevertheless combine to produce highly event-specific ensemble patterns that likely alter activity in downstream regions controlling emotional and autonomic tone. Since neuromodulators regulate the strength of the ensemble activity patterns, they would regulate the impact these patterns have on downstream targets. Through these mechanisms, the ACC may determine how strongly to react to the very events its ensembles represent. Pathologies arise when specific event-related representations gain excessive control over autonomic/emotional states., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Hippocampal synaptic plasticity includes both long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength, and has been implicated in shaping place field representations that form upon initial exposure to a novel environment. However, direct evidence causally linking either LTP or LTD to place fields remains limited. Here, we show that hippocampal LTD regulates the acute formation and maintenance of place fields using electrophysiology and blocking specifically LTD in freely-moving rats. We also show that exploration of a novel environment produces a widespread and pathway specific de novo synaptic depression in the dorsal hippocampus. Furthermore, disruption of this pathway-specific synaptic depression alters both the dynamics of place field formation and the stability of the newly formed place fields, affecting spatial memory in rats. These results suggest that activity-dependent synaptic depression is required for the acquisition and maintenance of novel spatial information.

In spite of being an intensive area of research focus, the anterior cingulate cortex (ACC) remains somewhat of an enigma. Many theories have focused on its role in various aspects of cognition yet surgically precise lesions of the ACC, used to treat severe emotional disorders in human patients, typically have no lasting effects on cognition. An alternative view is that the ACC has a prominent role in regulating autonomic states. This view is consistent with anatomical data showing that a main target of the ACC are regions involved in autonomic control and with the observation that stimulation of the ACC evokes changes in autonomic states in both animals and humans. From an electrophysiological perspective, ACC neurons appear able to represent virtually any event or internal state, even though there is not always a strong link between these representations and behavior. Ensembles of neurons form robust contextual representations that strongly influence how specific events are encoded. The activity patterns associated with these contextually-based event representations presumably impact activity in downstream regions that control autonomic state. As a result, the ACC may regulate the autonomic and perhaps emotional reactions to events it is representing. This event-based control of autonomic tone by the ACC would likely arise during all types of cognitive and affective processes, without necessarily being critical for any of them., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The ability to act on knowledge about the value of stimuli or actions factors into simple foraging behaviors as well as complex forms of decision-making. In striatal regions, action representations are thought to acquire value through a gradual (reinforcement-learning based) process. It is unclear whether this is also true for anterior cingulate cortex (ACC) where neuronal representations tend to change abruptly. We recorded from ensembles of ACC neurons as rats deduced which of 3 levers was rewarded each day. The rat's lever preferences changed gradually throughout the sessions as they eventually came to focus on the rewarded lever. Most individual neurons changed their responses to both rewarded and nonrewarded lever presses abruptly (<2 trials). These transitions occurred asynchronously across the population but peaked near the point where the rats began to focus on the rewarded lever. Because the individual transitions were asynchronous, the overall change at the population level appeared gradual. Abrupt transitions in action representations of ACC neurons may be part of a mechanism that alters choice strategies as new information is acquired., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Previous studies confirm that brief electrical stimulation of glutamatergic afferents from the ventral subiculum (vSub) can significantly enhance dopamine release in the ventral striatum for an extended duration (>20 min). However, the functional significance of this effect on motivated behavior remains to be specified. Here we tested the hypothesis that brief electrical stimulation of the ventral subiculum (20 Hz for 10 s) might increase effort expenditure for food rewards. Motivation was assessed by a progressive ratio lever pressing task, which requires continuous escalation of the numbers of lever presses to receive each subsequent sucrose pellet, eventually resulting in the failure to achieve the required ratio for a food reward. vSub stimulation at the start of a session did not affect the rate or total number of lever presses prior to reaching the "break point". In contrast, stimulation of the vSub with identical parameters on a post break point trial resulted in a significant increase in total responses. These findings demonstrate that activation of the vSub with parameters that modulate dopamine efflux in the nucleus accumbens can re-activate goal-directed behavior after failure to achieve a goal. Our data highlight a possible role for the vSub in the pathophysiology and potential treatment of motivational processes linked to psychiatric disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The anterior cingulate cortex (ACC) responds to outcomes of a positive or negative valence, but past studies typically focus on one valence or the other, making it difficult to know how opposing valences are disambiguated. We recorded from ACC neurons as rats received tones followed by aversive, appetitive or null outcomes. The responses to the different tones/outcomes were highly inter-mixed at the single neuron level but combined to produce robust valence-specific representations at the ensemble level. The valence-specific patterns far outlasted the tones and outcomes, persisting throughout the long inter-trial intervals (ITIs) and even throughout trial blocks. When the trials were interleaved, the valence-specific patterns abruptly shifted at the start of each new trial. Overall the aversive trials had the greatest impact on the neurons. Thus within the ACC, valence-specificity is largely an emergent property of ensembles and valence-specific representations can appear quickly and persist long after the initiating event.

Specialized brain structures encode spatial locations and movements, yet there is growing evidence that this information is also represented in the rodent medial prefrontal cortex (mPFC). Disambiguating such information from the encoding of other types of task-relevant information has proven challenging. To determine the extent to which movement and location information is relevant to mPFC neurons, tetrodes were used to record neuronal activity while limb positions, poses (i.e., recurring constellations of limb positions), velocity, and spatial locations were simultaneously recorded with two cameras every 200 ms as rats freely roamed in an experimental enclosure. Regression analyses using generalized linear models revealed that more than half of the individual mPFC neurons were significantly responsive to at least one of the factors, and many were responsive to more than one. On the other hand, each factor accounted for only a very small portion of the total spike count variance of any given neuron (<20% and typically <1%). Machine learning methods were used to analyze ensemble activity and revealed that ensembles were usually superior to the sum of the best neurons in encoding movements and spatial locations. Because movement and location encoding by individual neurons was so weak, it may not be such a concern for single-neuron analyses. Yet because these weak signals were so widely distributed across the population, this information was strongly represented at the ensemble level and should be considered in population analyses.

Connections between the hippocampus (HC) and medial prefrontal cortex (mPFC) are critical for working memory; however, the precise contribution of this pathway is a matter of debate. One suggestion is that it may stabilize retrospective memories of recently encountered task-relevant information. Alternatively, it may be involved in encoding prospective memories, or the internal representation of future goals. To explore these possibilities, simultaneous extracellular recordings were made from mPFC and HC of rats performing the delayed spatial win-shift on a radial maze. Each trial consisted of a training-phase (when 4 randomly chosen arms were open) and test phase (all 8 arms were open but only previously blocked arms contained food) separated by a 60-s delay. Theta power was highest during the delay, and mPFC units were more likely to become entrained to hippocampal theta as the delay progressed. Training and test phase performance were accurately predicted by a linear classifier, and there was a transition in classification for training-phase to test-phase activity patterns throughout the delay on trials where the rats performed well. These data suggest that the HC and mPFC become more strongly synchronized as mPFC circuits preferentially shift from encoding retrospective to prospective information., (© The Author 2017. Published by Oxford University Press.)

The function of the anterior cingulate cortex (ACC) remains controversial, yet many theories suggest a role in behavioral adaptation, partly because a robust event-related potential, the feedback-related negativity (FN), is evoked over the ACC whenever expectations are violated. We recorded from the ACC as rats performed a task identical to one that reliably evokes an FN in humans. A subset of neurons was found that encoded expected outcomes as abstract outcome representations. The degree to which a reward/non-reward outcome representation emerged during a trial depended on the history of outcomes that preceded it. A prediction error was generated on incongruent trials as the ensembles shifted from representing the expected to the actual outcome, at the same time point we have previously reported an FN in the local field potential. The results describe a novel mode of prediction error signaling by ACC neurons that is associated with the generation of an FN., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: The frontal cortex has been implicated in a number of cognitive and motivational processes, but understanding how individual neurons contribute to these processes is particularly challenging as they respond to a broad array of events (multiplexing) in a manner that can be dynamically modulated by the task context, i.e., adaptive coding (Duncan, 2001). Fundamental questions remain, such as how the flexibility gained through these mechanisms is balanced by the need for consistency and how the ensembles of neurons are coherently shaped by task demands. In the present study, ensembles of medial frontal cortex neurons were recorded from rats trained to perform three different operant actions either in two different sequences or two different physical environments. Single neurons exhibited diverse mixtures of responsivity to each of the three actions and these mixtures were abruptly altered by context/sequence switches. Remarkably, the overall responsivity of the population remained highly consistent both within and between context/sequences because the gains versus losses were tightly balanced across neurons and across the three actions. These data are consistent with a reallocation mixture model in which individual neurons express unique mixtures of selectivity for different actions that become reallocated as task conditions change. However, because the allocations and reallocations are so well balanced across neurons, the population maintains a low but highly consistent response to all actions. The frontal cortex may therefore balance consistency with flexibility by having ensembles respond in a fixed way to task-relevant actions while abruptly reconfiguring single neurons to encode "actions in context.", Significance Statement: Flexible modes of behavior involve performance of similar actions in contextually relevant ways. The present study quantified the changes in how rat medial frontal cortex neurons respond to the same actions when performed in different task contexts (sequences or environments). Most neurons altered the mixture of actions they were responsive to in different contexts or sequences. Nevertheless, the responsivity profile of the ensemble remained fixed as did the ability of the ensemble to differentiate between the three actions. These mechanisms may help to contextualize the manner in which common events are represented across different situations., (Copyright © 2016 the authors 0270-6474/16/368258-15$15.00/0.)

Working memory dysfunction is an especially debilitating symptom in schizophrenia. The NMDA antagonist ketamine has been successfully used to model working memory deficits in both rodents and nonhuman primates, but how it affects the strength and the consistency of working memory representations remains unclear. Here we recorded single-neuron activity in the lateral prefrontal cortex of macaque monkeys before and after the administration of subanesthetic doses of ketamine in a rule-based working memory task. The rule was instructed with a color cue before each delay period and dictated the correct prosaccadic or antisaccadic response to a peripheral stimulus appearing after the delay. We found that acute ketamine injections both weakened the rule signal across all delay periods and amplified the trial-to-trial variance in neural activities (i.e., noise), both within individual neurons and at the ensemble level, resulting in impaired performance. In the minority of postinjection trials when the animals responded correctly, the preservation of the signal strength during the delay periods was predictive of their subsequent success. Our findings suggest that NMDA receptor function may be critical for establishing the optimal signal-to-noise ratio in information representation by ensembles of prefrontal cortex neurons., Significance Statement: In schizophrenia patients, working memory deficit is highly debilitating and currently without any efficacious treatment. An improved understanding of the pathophysiology of this symptom may provide critical information to treatment development. The NMDA antagonist ketamine, when injected at a subanesthetic dose, produces working memory deficit and other schizophrenia-like symptoms in humans and other animals. Here we investigated the effects of ketamine on the representation of abstract rules by prefrontal neurons, while macaque monkeys held the rules in working memory before responding accordingly. We found that ketamine weakened the signal-to-noise ratio in rule representation by simultaneously weakening the signal and augmenting noise. Both processes may be relevant in an effective therapy for working memory impairment in schizophrenia., (Copyright © 2015 the authors 0270-6474/15/3511612-11$15.00/0.)

Modulation of neural activity by monoamine neurotransmitters is thought to play an essential role in shaping computational neurodynamics in the neocortex, especially in prefrontal regions. Computational theories propose that monoamines may exert bidirectional (concentration-dependent) effects on cognition by altering prefrontal cortical attractor dynamics according to an inverted U-shaped function. To date, this hypothesis has not been addressed directly, in part because of the absence of appropriate statistical methods required to assess attractor-like behavior in vivo. The present study used a combination of advanced multivariate statistical, time series analysis, and machine learning methods to assess dynamic changes in network activity from multiple single-unit recordings from the medial prefrontal cortex (mPFC) of rats while the animals performed a foraging task guided by working memory after pretreatment with different doses of d-amphetamine (AMPH), which increases monoamine efflux in the mPFC. A dose-dependent, bidirectional effect of AMPH on neural dynamics in the mPFC was observed. Specifically, a 1.0 mg/kg dose of AMPH accentuated separation between task-epoch-specific population states and convergence toward these states. In contrast, a 3.3 mg/kg dose diminished separation and convergence toward task-epoch-specific population states, which was paralleled by deficits in cognitive performance. These results support the computationally derived hypothesis that moderate increases in monoamine efflux would enhance attractor stability, whereas high frontal monoamine levels would severely diminish it. Furthermore, they are consistent with the proposed inverted U-shaped and concentration-dependent modulation of cortical efficiency by monoamines., (Copyright © 2015 the authors 0270-6474/15/3510172-16$15.00/0.)

The persistent Na(+) current (I(Nap)) is believed to be an important target of dopamine modulation in prefrontal cortex (PFC) neurons. While past studies have tested the effects of dopamine on I(Nap), the results have been contradictory largely because of difficulties in measuring I(Nap) using somatic whole-cell recordings. To circumvent these confounds we used the cell-attached patch-clamp technique to record single Na(+) channels from the soma, proximal dendrite (PD) or proximal axon (PA) of intact prefrontal layer V pyramidal neurons. Under baseline conditions, numerous well resolved Na(+) channel openings were recorded that exhibited an extrapolated reversal potential of 73 mV, a slope conductance of 14-19 pS and were blocked by tetrodotoxin (TTX). While similar in most respects, the propensity to exhibit prolonged bursts lasting >40 ms was many fold greater in the axon than the soma or dendrite. Bath application of the D1/D5 receptor agonist SKF81297 shifted the ensemble current activation curve leftward and increased the number of late events recorded from the PD but not the soma or PA. However, the greatest effect was on prolonged bursting where the D1/D5 receptor agonist increased their occurrence 3 fold in the PD and nearly 7 fold in the soma, but not at all in the PA. As a result, D1/D5 receptor activation equalized the probability of prolonged burst occurrence across the proximal axosomatodendritic region. Therefore, D1/D5 receptor modulation appears to be targeted mainly to Na(+) channels in the PD/soma and not the PA. By circumventing the pitfalls of previous attempts to study the D1/D5 receptor modulation of I(Nap), we demonstrate conclusively that D1/D5 receptor activation can increase the I(Nap) generated proximally, however questions still remain as to how D1/D5 receptor modulates Na(+) currents in the more distal initial segment where most of the I Nap is normally generated.

The feedback-related negativity (FRN) refers to a difference in the human event-related potential (ERP) elicited by feedback indicating success versus failure: the difference appears negative when subtracting the success ERP from the failure ERP (Miltner et al., 1997). Although source localization techniques (e.g., BESA) suggest that the FRN is produced in the ACC, the inverse problem (that any given scalp distribution can be produced by an infinite number of possible dipole configurations) limits the certainty of this conclusion. The inverse problem can be circumvented by directly recording from the ACC in animal models. Although a non-human primate homologue of the FRN has been observed in the macaque monkey (e.g. Emeric et al., 2008), a homologue of the FRN has yet to be identified in rodents. We recorded local field potentials (LFPs) directly from the ACC in 6 rodents in a task based on the FRN paradigm. The animals were trained to poke their nose into a lighted port and received a feedback smell indicating whether or not a reward pellet would drop 1.5s later. We observed a FRN-like effect time-locked to the feedback scent whereby the LFP to feedback predicting no-reward was significantly more negative than the LFP to feedback predicting reward. This deflection began on average 130ms before behavioral changes in response to the feedback. Thus, we provide the first evidence of the existence of a rodent homologue of the FRN., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The function of a given brain region is often defined by the coding properties of its individual neurons, yet how this information is combined at the ensemble level is an equally important consideration. We recorded multiple neurons from the anterior cingulate cortex (ACC) and the dorsal striatum (DS) simultaneously as rats performed different sequences of the same three actions. Sequence and lever decoding was markedly similar on a per-neuron basis in the two regions. At the ensemble level, sequence-specific representations in the DS appeared synchronously, but transiently, along with the representation of lever location, whereas these two streams of information appeared independently and asynchronously in the ACC. As a result, the ACC achieved superior ensemble decoding accuracy overall. Thus, the manner in which information was combined across neurons in an ensemble determined the functional separation of the ACC and DS on this task.

When performing sequences of actions, we constantly keep track of our current position in the sequence relative to the overall goal. The present study searched for neural representations of sequence progression in corticostriatal circuits. Neurons within the anterior cingulate cortex (ACC) and its target region in the dorsal striatum (DS) were recorded from simultaneously as rats performed different sequences of lever presses. We analyzed the responses of the neurons to presses occurring in the "first," "second," or "third" serial position regardless of the particular sequence or physical levers. Principal component analysis revealed that the main source of firing rate variance in the ACC was a smooth ramp-like change as the animal progressed through the sequence toward the reward. No such smooth-ramping activity was observed in DS ensembles as firing tended to be tightly linked to each action. In the ACC, the progression in firing was observed only for correct choices and not errors, whereas in the DS, firing associated with each action in a sequence was similar regardless of whether the action was correct or not. Therefore, different forms of a signal exist within corticostriatal circuits that evolve across a sequence of actions, with DS ensembles tracking every action and ACC ensembles tracking actual progress toward the goal.

Although there are numerous theories regarding anterior cingulate cortex (ACC) function, most suggest that it is involved in some form of action or outcome processing. The present study characterized the dominant patterns of ACC activity on a task in which actions and outcomes could vary independently. Patterns of activity were detected using a modified form of principal component analysis (PCA), termed constrained PCA in which a regression procedure was applied prior to PCA to eliminate the contribution of nontask-related activity. When trials were grouped according to outcome, a PC was found in all subjects and sessions that had large fluctuations during actions but only differentiated correct versus error trials prior to the end of the delay and again at time of the outcome. Another PC was always present that separated right from left lever presses, but only around the time of the actual lever press. Individual neurons exhibited significant selectivities for trials involving different actions and/or outcomes. Of the ACC neurons that exhibited significant outcome selectivity, the majority fired more on error trials. The present study revealed separate as well as integrated action and outcome monitoring in the ACC, especially, although not exclusively, under conditions when an error is likely.

Foraging typically involves two distinct phases, an exploration phase where an organism explores its local environment in search of needed resources and an exploitation phase where a discovered resource is consumed. The behavior and cognitive requirements of exploration and exploitation are quite different and yet organisms can quickly and efficiently switch between them many times during a foraging bout. The present study investigated neural activity state dynamics in the anterior cingulate sub-region of the rat medial prefrontal cortex (mPFC) when a reliable food source was introduced into an environment. Distinct and largely independent states were detected using a Hidden Markov Model (HMM) when food was present or absent in the environment. Measures of neural entropy or complexity decreased when rats went from exploring the environment to exploiting a reliable food source. Exploration in the absence of food was associated with many weak activity states, while bouts of food consumption were characterized by fewer stronger states. Widespread activity state changes in the mPFC may help to inform foraging decisions and focus behavior on what is currently most prominent or valuable in the environment.

Contextual representations serve to guide many aspects of behavior and influence the way stimuli or actions are encoded and interpreted. The medial prefrontal cortex (mPFC), including the anterior cingulate subregion, has been implicated in contextual encoding, yet the nature of contextual representations formed by the mPFC is unclear. Using multiple single-unit tetrode recordings in rats, we found that different activity patterns emerged in mPFC ensembles when animals moved between different environmental contexts. These differences in activity patterns were significantly larger than those observed for hippocampal ensembles. Whereas ≈11% of mPFC cells consistently preferred one environment over the other across multiple exposures to the same environments, optimal decoding (prediction) of the environmental setting occurred when the activity of up to ≈50% of all mPFC neurons was taken into account. On the other hand, population activity patterns were not identical upon repeated exposures to the very same environment. This was partly because the state of mPFC ensembles seemed to systematically shift with time, such that we could sometimes predict the change in ensemble state upon later reentry into one environment according to linear extrapolation from the time-dependent shifts observed during the first exposure. We also observed that many strongly action-selective mPFC neurons exhibited a significant degree of context-dependent modulation. These results highlight potential differences in contextual encoding schemes by the mPFC and hippocampus and suggest that the mPFC forms rich contextual representations that take into account not only sensory cues but also actions and time.

The mesocortical pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) plays a critical role in a number of cognitive and emotional processes. While this pathway has been traditionally viewed as dopaminergic, recent data indicate that a considerable proportion of rostromedial VTA neurons possess markers for glutamate transmission. However, the relative density of the glutamatergic projection to the PFC from these rostromedial regions is unknown. In the present study, anterograde tracer injections into 4 ventral midbrain subregions were coupled with immunohistochemical analysis of labeled axons in PFC for markers of dopamine (DA; tyrosine hydroxylase [TH]) and glutamate (vesicular glutamate transporter 2; VGLUT2). We found that while tracer injections into the interfascicular nucleus produced labeled fibers in the PFC that were mainly TH positive, tracer injections into the rostral linear nucleus, rostral VTA, and parabrachial pigmented nucleus produced labeled fibers in PFC that contained mainly VGLUT2-positive rather than TH-positive varicosities. When viewed in the light of the previously documented strong γ-aminobutyric acidergic component, it would seem that the rostromedial mesocortical projection is actually an amino acid pathway that in addition has a DA component.

Background: Dopamine (DA) and serotonin (5-HT) are released in cortex under similar circumstances, and many psychiatric drugs bind to both types of receptors, yet little is known about how they interact., Methods: To characterize the nature of these interactions, the current study used in vitro patch-clamp recordings to measure the effects of DA and/or 5-HT on pyramidal cells in layer V of the medial prefrontal cortex., Results: Either DA or 5-HT applied in isolation increased the evoked excitability of prefrontal cortex neurons, as shown previously. Coapplication of DA and 5-HT produced either a larger increase in excitability than when either was given alone or a significant decrease that was never observed when either was given alone. Dopamine or 5-HT also "primed" neurons to respond in an exaggerated manner to the subsequent application of the other monoamine., Conclusions: These data reveal the unappreciated interactive nature of neuromodulation in cortex by showing that the combined effects of DA and 5-HT can be different from their effects recorded in isolation. On the basis of these findings, we present a theory of how DA and 5-HT might synergistically modulate cortical circuits during various tasks., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A common theoretical view is that attractor-like properties of neuronal dynamics underlie cognitive processing. However, although often proposed theoretically, direct experimental support for the convergence of neural activity to stable population patterns as a signature of attracting states has been sparse so far, especially in higher cortical areas. Combining state space reconstruction theorems and statistical learning techniques, we were able to resolve details of anterior cingulate cortex (ACC) multiple single-unit activity (MSUA) ensemble dynamics during a higher cognitive task which were not accessible previously. The approach worked by constructing high-dimensional state spaces from delays of the original single-unit firing rate variables and the interactions among them, which were then statistically analyzed using kernel methods. We observed cognitive-epoch-specific neural ensemble states in ACC which were stable across many trials (in the sense of being predictive) and depended on behavioral performance. More interestingly, attracting properties of these cognitively defined ensemble states became apparent in high-dimensional expansions of the MSUA spaces due to a proper unfolding of the neural activity flow, with properties common across different animals. These results therefore suggest that ACC networks may process different subcomponents of higher cognitive tasks by transiting among different attracting states.

There has been considerable interest in the importance of oscillations in the brain and in how these oscillations relate to the firing of single neurons. Recently a number of studies have shown that the spiking of individual neurons in the medial prefrontal cortex (mPFC) become entrained to the hippocampal (HPC) theta rhythm. We recently showed that theta-entrained mPFC cells lost theta-entrainment specifically on error trials even though the firing rates of these cells did not change (Hyman et al., 2010). This implied that the level of HPC theta-entrainment of mPFC units was more predictive of trial outcome than differences in firing rates and that there is more information encoded by the mPFC on working memory tasks than can be accounted for by a simple rate code. Nevertheless, the functional meaning of mPFC entrainment to HPC theta remains a mystery. It is also unclear as to whether there are any differences in the nature of the information encoded by theta-entrained and non-entrained mPFC cells. In this review we discuss mPFC entrainment to HPC theta within the context of previous results as well as provide a more detailed analysis of the Hyman et al. (2010) data set. This re-analysis revealed that theta-entrained mPFC cells selectively encoded a variety of task-relevant behaviors and stimuli while never theta-entrained mPFC cells were most strongly attuned to errors or the lack of expected rewards. In fact, these error responsive neurons were responsible for the error representations exhibited by the entire ensemble of mPFC neurons. A theta reset was also detected in the post-error period. While it is becoming increasingly evident that mPFC neurons exhibit correlates to virtually all cues and behaviors, perhaps phase-locking directs attention to the task-relevant representations required to solve a spatially based working memory task while the loss of theta-entrainment at the start of error trials may represent a shift of attention away from these representations. The subsequent theta reset following error commission, when coupled with the robust responses of never theta-entrained cells, could produce a potent error-evoked signal used to alert the rat to changes in the relationship between task-relevant cues and reward expectations.

One of the most intriguing aspects of adaptive behavior involves the inference of regularities and rules in ever-changing environments. Rules are often deduced through evidence-based learning which relies on the prefrontal cortex (PFC). This is a highly dynamic process, evolving trial by trial and therefore may not be adequately captured by averaging single-unit responses over numerous repetitions. Here, we employed advanced statistical techniques to visualize the trajectories of ensembles of simultaneously recorded medial PFC neurons on a trial-by-trial basis as rats deduced a novel rule in a set-shifting task. Neural populations formed clearly distinct and lasting representations of familiar and novel rules by entering unique network states. During rule acquisition, the recorded ensembles often exhibited abrupt transitions, rather than evolving continuously, in tight temporal relation to behavioral performance shifts. These results support the idea that rule learning is an evidence-based decision process, perhaps accompanied by moments of sudden insight., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, but its mechanisms of action remain controversial. DA is thought to increase signal gain in active networks according to an inverted U dose-response curve, and these effects may depend on both tonic and phasic release of DA from midbrain ventral tegmental area (VTA) neurons., Methodology/principal Findings: We used patch-clamp recordings in organotypic co-cultures of the PFC, hippocampus and VTA to study DA modulation of spontaneous network activity in the form of Up-states and signals in the form of synchronous EPSP trains. These cultures possessed a tonic DA level and stimulation of the VTA evoked DA transients within the PFC. The addition of high (> or = 1 microM) concentrations of exogenous DA to the cultures reduced Up-states and diminished excitatory synaptic inputs (EPSPs) evoked during the Down-state. Increasing endogenous DA via bath application of cocaine also reduced Up-states. Lower concentrations of exogenous DA (0.1 microM) had no effect on the up-state itself, but they selectively increased the efficiency of a train of EPSPs to evoke spikes during the Up-state. When the background DA was eliminated by depleting DA with reserpine and alpha-methyl-p-tyrosine, or by preparing corticolimbic co-cultures without the VTA slice, Up-states could be enhanced by low concentrations (0.1-1 microM) of DA that had no effect in the VTA containing cultures. Finally, in spite of the concentration-dependent effects on Up-states, exogenous DA at all but the lowest concentrations increased intracellular current-pulse evoked firing in all cultures underlining the complexity of DA's effects in an active network., Conclusions/significance: Taken together, these data show concentration-dependent effects of DA on global PFC network activity and they demonstrate a mechanism through which optimal levels of DA can modulate signal gain to support cognitive functioning.

Background and Rationale: Genetic variations in catechol-O-methyl transferase (COMT) or administration of COMT inhibitors have a robust impact on cognition and executive function in humans. The COMT enzyme breaks down extracellular dopamine (DA) and has a particularly important role in the prefrontal cortex (PFC) where DA transporters are sparse. As such, the beneficial cognitive effects of the COMT inhibitor tolcapone are postulated to be the result of increased bioavailability of DA in the PFC. Furthermore, it has been shown previously that COMT inhibitors increase pharmacologically evoked DA but do not affect basal levels in the PFC., Objectives: The current study characterized the ability of tolcapone to increase DA release in response to behaviorally salient stimuli and improve performance of the delayed spatial win-shift (DSWSh) task., Results and Conclusions: Tolcapone enhanced PFC DA efflux associated with the anticipation and consumption of food when compared to saline controls. Chronic and acute treatment with tolcapone also reduced the number of errors committed during acquisition of the DSWSh. However, no dissociable effects were observed in experiments designed to selectively assay encoding or recall in well-trained animals, as both experiments showed improvement with tolcapone treatment. Taken together, these data suggest a generalized positive influence on cognition. Furthermore, these data support the conclusion of Apud and Weinberger (CNS Drugs 21:535-557, 2007) that agents which selectively potentiate PFC DA release may confer cognitive enhancement without the unwanted side effects produced by drugs that increase basal DA levels in cortical and subcortical brain regions.

There is now general consensus that at least some of the cognitive deficits in schizophrenia are related to dysfunctions in the prefrontal cortex (PFC) dopamine (DA) system. At the cellular and synaptic level, the effects of DA in PFC via D1- and D2-class receptors are highly complex, often apparently opposing, and hence difficult to understand with regard to their functional implications. Biophysically realistic computational models have provided valuable insights into how the effects of DA on PFC neurons and synaptic currents as measured in vitro link up to the neural network and cognitive levels. They suggest the existence of two discrete dynamical regimes, a D1-dominated state characterized by a high energy barrier among different network patterns that favors robust online maintenance of information and a D2-dominated state characterized by a low energy barrier that is beneficial for flexible and fast switching among representational states. These predictions are consistent with a variety of electrophysiological, neuroimaging, and behavioral results in humans and nonhuman species. Moreover, these biophysically based models predict that imbalanced D1:D2 receptor activation causing extremely low or extremely high energy barriers among activity states could lead to the emergence of cognitive, positive, and negative symptoms observed in schizophrenia. Thus, combined experimental and computational approaches hold the promise of allowing a detailed mechanistic understanding of how DA alters information processing in normal and pathological conditions, thereby potentially providing new routes for the development of pharmacological treatments for schizophrenia.

There is a long-standing debate about whether rats have what could be considered a prefrontal cortex (PFC) and, if they do, what its primate homologue is. Anatomical evidence supports the view that the rat medial PFC is related to both the primate anterior cingulate cortex (ACC) and the dorsolateral PFC. Functionally the primate and human ACC are believed to be involved in the monitoring of actions and outcomes to guide decisions especially in challenging situations where cognitive conflict and errors arise. In contrast, the dorsolateral PFC is responsible for the maintenance and manipulation of goal-related items in memory in the service of planning, problem solving, and predicting forthcoming events. Recent multiple single-unit recording studies in rats have reported strong correlates of motor planning, movement and reward anticipation analogous to what has been observed in the primate ACC. There is also emerging evidence that rats may partly encode information over delays using body posture or variations in running path as embodied strategies, and that these are the aspects tracked by medial PFC neurons. The primate PFC may have elaborated on these rudimentary functions by carrying them over to more abstract levels of mental representation, more independent from somatic or other external mnemonic cues, and allowing manipulation of mental contents outside specific task contexts. Therefore, from an electrophysiological and computational perspective, the rat medial PFC seems to combine elements of the primate ACC and dorsolateral PFC at a rudimentary level. In primates, these functions may have formed the building blocks required for abstract rule encoding during the expansion of the cortex dorsolaterally.

Successful decision making requires an ability to monitor contexts, actions, and outcomes. The anterior cingulate cortex (ACC) is thought to be critical for these functions, monitoring and guiding decisions especially in challenging situations involving conflict and errors. A number of different single-unit correlates have been observed in the ACC that reflect the diverse cognitive components involved. Yet how ACC neurons function as an integrated network is poorly understood. Here we show, using advanced population analysis of multiple single-unit recordings from the rat ACC during performance of an ecologically valid decision-making task, that ensembles of neurons move through different coherent and dissociable states as the cognitive requirements of the task change. This organization into distinct network patterns with respect to both firing-rate changes and correlations among units broke down during trials with numerous behavioral errors, especially at choice points of the task. These results point to an underlying functional organization into cell assemblies in the ACC that may monitor choices, outcomes, and task contexts, thus tracking the animal's progression through "task space."

Dopamine (DA) exerts a strong influence on inhibition in prefrontal cortex. The main cortical interneuron subtype targeted by DA are fast-spiking gamma-aminobutyric acidergic (GABAergic) cells that express the calcium-binding protein parvalbumin. D1 stimulation depolarizes these interneurons and increases excitability evoked by current injection. The present study examined whether this direct DA-dependent modulation of fast-spiking interneurons involves DARPP-32. Whole-cell patch-clamp recordings were made from fast-spiking interneurons in brain slices from DARPP-32 knockout (KO) mice, wild-type mice, and rats. Low concentrations of DA (100 nM) increased interneuron excitability via D1 receptors, protein kinase A, and cyclic adenosine 3',5'-monophosphate in slices from both normal and DARPP-32 KO mice. Immunohistochemical staining of slices from normal animals revealed a lack of colocalization of DARPP-32 with calcium-binding proteins selective for fast-spiking interneurons, indicating that these interneurons do not express DARPP-32. Therefore, although DARPP-32 impacts cortical inhibition through a previously demonstrated D2-dependent regulation of GABAergic currents in pyramidal cells, it is not involved in the direct D1-mediated regulation of fast-spiking interneurons.

Diminished activity within the prefrontal cortex (PFC) has been associated with many of the cognitive deficits that are observed in schizophrenia. It has been hypothesized that antipsychotic drugs (APDs) used to treat schizophrenia restore normal activity by antagonizing the dopamine (DA) D2 receptor, which is also known to modulate key ionic currents in the PFC. However, the hypothesis that an under-active cortical DA system is responsible for schizophrenic symptoms has been challenged by evidence that newer atypical APDs are weak antagonists at the D2 receptor but potent antagonists at the serotonin (5-HT) 2A receptor . This review examines how DA and 5-HT modulate cortical activity and how they may interact in ways that are relevant to schizophrenia. It is concluded that although D2 receptor antagonism remains a critical factor in restoring impaired cortical activity, effects on 5-HT receptors may act in a synergistic manner on NMDA and GABA currents to potentiate antipsychotic actions in the PFC.

Background: This review discusses evidence that cells in the mesocortical dopamine (DA) system influence information processing in target areas across three distinct temporal domains., Discussions: Phasic bursting of midbrain DA neurons may provide temporally precise information about the mismatch between expected and actual rewards (prediction errors) that has been hypothesized to serve as a learning signal in efferent regions. However, because DA acts as a relatively slow modulator of cortical neurotransmission, it is unclear whether DA can indeed act to precisely transmit prediction errors to prefrontal cortex (PFC). In light of recent physiological and anatomical evidence, we propose that corelease of glutamate from DA and/or non-DA neurons in the VTA could serve to transmit this temporally precise signal. In contrast, DA acts in a protracted manner to provide spatially and temporally diffuse modulation of PFC pyramidal neurons and interneurons. This modulation occurs first via a relatively rapid depolarization of fast-spiking interneurons that acts on the order of seconds. This is followed by a more protracted modulation of a variety of other ionic currents on timescales of minutes to hours, which may bias the manner in which cortical networks process information. However, the prolonged actions of DA may be curtailed by counteracting influences, which likely include opposing actions at D1 and D2-like receptors that have been shown to be time- and concentration-dependent. In this way, the mesocortical DA system optimizes the characteristics of glutamate, GABA, and DA neurotransmission both within the midbrain and cortex to communicate temporally precise information and to modulate network activity patterns on prolonged timescales.

Prefrontal cortex (PFC) dopamine D1/5 receptors modulate long- and short-term neuronal plasticity that may contribute to cognitive functions. Synergistic to synaptic strength modulation, direct postsynaptic D1/5 receptor activation also modulates voltage-dependent ionic currents that regulate spike firing, thus altering the neuronal input-output relationships in a process called long-term potentiation of intrinsic excitability (LTP-IE). Here, the intracellular signals that mediate this D1/5 receptor-dependent LTP-IE were determined using whole cell current-clamp recordings in layer V/VI rat pyramidal neurons from PFC slices. After blockade of all major amino acid receptors (V(hold) = -65 mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist SKF81297 (0.2-50 microM) induced LTP-IE, as shown by a prolonged (>40 min) increase in depolarizing pulse-evoked spike firing. Pretreatment with the D1/5 antagonist SCH23390 (1 microM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The SKF81297-induced LTP-IE was significantly attenuated by Cd(2+), [Ca(2+)](i) chelation, by inhibition of phospholipase C, protein kinase-C, and Ca(2+)/calmodulin kinase-II, but not by inhibition of adenylate cyclase, protein kinase-A, MAP kinase, or L-type Ca(2+) channels. Thus this form of D1/5 receptor-mediated LTP-IE relied on Ca(2+) influx via non-L-type Ca(2+) channels, activation of PLC, intracellular Ca(2+) elevation, activation of Ca(2+)-dependent CaMKII, and PKC to mediate modulation of voltage-dependent ion channel(s). This D1/5 receptor-mediated modulation by PKC coexists with the previously described PKA-dependent modulation of K(+) and Ca(2+) currents to dynamically regulate overall excitability of PFC neurons.

While Dale's principle of "one neuron, one neurotransmitter" has undergone revisions to incorporate evidence of the corelease of atypical neurotransmitters such as neuropeptides, the corelease of classical neurotransmitters has only recently been realized. Surprisingly, numerous studies now indicate that the corelease of neurotransmitters in the mammalian central nervous system is not an obscure and rare phenomenon but is widespread and involves most classical neurotransmitters systems. However, the suggestion that glutamate can be coreleased with dopamine (DA) has remained controversial. Furthermore, glutamate-DA cotransmission has not yet been seriously considered in the context of the neurocircuitry of addiction. If glutamate is in fact coreleased with DA as some evidence now suggests, this may have significant implications for advancing our understanding of the interactive role that these 2 neurotransmitters play in cognitive and reward processes. In this commentary, we review the evidence for and against glutamate as a cotransmitter and discuss the potential role of glutamate-DA corelease in addiction. In particular, we describe a recently proposed model in which coreleased glutamate transmits a temporally precise prediction error signal of reward described by Schultz et al., whereas the function of coreleased DA is to exert prolonged modulatory influences on neuronal activity. In addition, we suggest that as alcohol consumption transitions from recreational use to addiction, there is a corresponding transition in the reward valence signal from better than predicted to worse than predicted.

Working memory has often been modeled and conceptualized as a kind of binary (bistable) memory switch, where stimuli turn on plateau-like persistent activity in subsets of cells, in line with many in vivo electrophysiological reports. A potentially related form of bistability, termed up- and down-states, has been studied with regard to its synaptic and ionic basis in vivo and in reduced cortical preparations. Also single cell mechanisms for producing bistability have been proposed and investigated in brain slices and computationally. Recently, however, it has been emphasized that clear plateau-like bistable activity is rather rare during working memory tasks, and that neurons exhibit a multitude of different temporally unfolding activity profiles and temporal structure within their spiking dynamics. Hence, working memory seems to be a highly dynamical neural process with yet unknown mappings from dynamical to computational properties. Empirical findings on ramping activity profiles and temporal structure will be reviewed, as well as neural models that attempt to account for it and its computational significance. Furthermore, recent in vivo, neural culture, and in vitro preparations will be discussed that offer new possibilities for studying the biophysical mechanisms underlying computational processes during working memory. These preparations have revealed additional evidence for temporal structure and spatio-temporally organized attractor states in cortical networks, as well as for specific computational properties that may characterize synaptic processing during high-activity states as during working memory. Together such findings may lay the foundations for highly dynamical theories of working memory based on biophysical principles.

Dopaminergic regulation of primate dorsolateral prefrontal cortex (PFC) activity is essential for cognitive functions such as working memory. However, the cellular mechanisms of dopamine neuromodulation in PFC are not well understood. We have studied the effects of dopamine receptor activation during persistent stimulation of excitatory inputs onto fast-spiking GABAergic interneurons in monkey PFC. Stimulation at 20 Hz induced short-term excitatory postsynaptic potential (EPSP) depression. The D1 receptor agonist SKF81297 (5 microM) significantly reduced the amplitude of the first EPSP but not of subsequent responses in EPSP trains, which still displayed significant depression. Dopamine (DA; 10 microM) effects were similar to those of SKF81297 and were abolished by the D1 antagonist SCH23390 (5 microM), indicating a D1 receptor-mediated effect. DA did not alter miniature excitatory postsynaptic currents, suggesting that its effects were activity dependent and presynaptic action potential dependent. In contrast to previous findings in pyramidal neurons, in fast-spiking cells, contribution of N-methyl-D-aspartate receptors to EPSPs at subthreshold potentials was not significant and fast-spiking cell depolarization decreased EPSP duration. In addition, DA had no significant effects on temporal summation. The selective decrease in the amplitude of the first EPSP in trains delivered every 10 s suggests that in fast-spiking neurons, DA reduces the amplitude of EPSPs evoked at low frequency but not of EPSPs evoked by repetitive stimulation. DA may therefore improve detection of EPSP bursts above background synaptic activity. EPSP bursts displaying short-term depression may transmit spike-timing-dependent temporal codes contained in presynaptic spike trains. Thus DA neuromodulation may increase the signal-to-noise ratio at fast-spiking cell inputs.

Withdrawal from chronic cocaine reduces extracellular glutamate levels in the nucleus accumbens by decreasing cystine/glutamate exchange (xc-). Activating xc- with N-acetylcysteine restores extracellular glutamate and prevents cocaine-induced drug seeking. It was hypothesized that the activation of xc- prevents drug seeking by increasing glutamatergic tone on presynaptic group II metabotropic glutamate receptors (mGluR2/3) and thereby inhibiting excitatory transmission. In the first experiment, the capacity of glutamate derived from xc- to regulate excitatory transmission via mGluR2/3 was determined. Physiological levels of cystine (100-300 nm) were restored to acute tissue slices from the nucleus accumbens or prefrontal cortex. Cystine increased glutamate efflux and decreased miniature EPSC (mEPSC) and spontaneous EPSC (sEPSC) frequency as well as evoked EPSC amplitude. These effects of cystine were presynaptic, because there was no change in mEPSC or sEPSC amplitude, and an increase in the evoked EPSC paired-pulse facilitation ratio. The cystine-induced reduction in EPSCs was reversed by blocking either xc- or mGluR2/3. In the second experiment, blocking mGluR2/3 prevented the ability of N-acetylcystine to inhibit the reinstatement of drug seeking in rats trained to self-administer cocaine. These data demonstrate that nonsynaptic glutamate derived from xc- modulates synaptic glutamate release and thereby regulates cocaine-induced drug seeking.

In vivo extracellular recording studies have traditionally shown that dopamine (DA) transiently inhibits prefrontal cortex (PFC) neurons, yet recent biophysical measurements in vitro indicate that DA enhances the evoked excitability of PFC neurons for prolonged periods. Moreover, although DA neurons apparently encode stimulus salience by transient alterations in firing, the temporal properties of the PFC DA signal associated with various behaviors is often extraordinarily prolonged. The present study used in vivo electrophysiological and electrochemical measures to show that the mesocortical system produces a fast non-DA-mediated postsynaptic response in the PFC that appears to be initiated by glutamate. In contrast, short burst stimulation of mesocortical DA neurons that produced transient (<4 s) DA release in the PFC caused a simultaneous reduction in spontaneous firing (consistent with extracellular in vivo recordings) and a form of DA-induced potentiation in which evoked firing was increased for tens of minutes (consistent with in vitro measurements). We suggest that the mesocortical system might transmit fast signals about reward or salience via corelease of glutamate, whereas the simultaneous prolonged DA-mediated modulation of firing biases the long-term processing dynamics of PFC networks.

Typically, D1 and D2 dopamine (DA) receptors exert opposing actions on intracellular signaling molecules and often have disparate physiological effects; however, the factors determining preferential activation of D1 versus D2 signaling are not clear. Here, in vitro patch-clamp recordings show that DA concentration is a critical determinant of D1 versus D2 signaling in prefrontal cortex (PFC). Low DA concentrations (<500 nm) enhance IPSCs via D1 receptors, protein kinase A, and cAMP. Higher DA concentrations (>1 microm) decrease IPSCs via the following cascade: D2-->G(i)-->platelet-derived growth factor receptor--> increase phospholipase C--> increase IP3--> increase Ca2+--> decrease dopamine and cAMP-regulated phosphoprotein-32--> increase protein phosphatase 1/2A--> decrease GABA(A). Blockade of any molecule in the D2-linked pathway reveals a D1-mediated increase in IPSCs, suggesting that D1 effects are occluded at higher DA concentrations by this D2-mediated pathway. Thus, DA concentration, by acting through separate signaling cascades, may determine the relative amount of cortical inhibition and thereby differentially regulate the tuning of cortical networks.

Mesocortical [corrected] dopamine (DA) inputs to the prefrontal cortex (PFC) play a critical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symptoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose-response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.

The D1-like (D1, D5) and D2-like (D2, D3, D4) classes of dopamine receptors each has shared signaling properties that contribute to the definition of the receptor class, although some differences among subtypes within a class have been identified. D1-like receptor signaling is mediated chiefly by the heterotrimeric G proteins Galphas and Galphaolf, which cause sequential activation of adenylate cyclase, cylic AMP-dependent protein kinase, and the protein phosphatase-1 inhibitor DARPP-32. The increased phosphorylation that results from the combined effects of activating cyclic AMP-dependent protein kinase and inhibiting protein phosphatase 1 regulates the activity of many receptors, enzymes, ion channels, and transcription factors. D1 or a novel D1-like receptor also signals via phospholipase C-dependent and cyclic AMP-independent mobilization of intracellular calcium. D2-like receptor signaling is mediated by the heterotrimeric G proteins Galphai and Galphao. These pertussis toxin-sensitive G proteins regulate some effectors, such as adenylate cyclase, via their Galpha subunits, but regulate many more effectors such as ion channels, phospholipases, protein kinases, and receptor tyrosine kinases as a result of the receptor-induced liberation of Gbetagamma subunits. In addition to interactions between dopamine receptors and G proteins, other protein:protein interactions such as receptor oligomerization or receptor interactions with scaffolding and signal-switching proteins are critical for regulation of dopamine receptor signaling.

Persistent activity is observed in many cortical and subcortical brain regions, and may subserve a variety of functions. Within the prefrontal cortex (PFC), neurons transiently maintain information in working memory via persistent activity patterns; however, the mechanisms involved are largely unknown. The present study used intracellular recordings from deep layer PFC neurons in vivo and patch-clamp recordings from PFC neurons in organotypic brain slice cultures to examine the ionic mechanisms underlying persistent activity states evoked by various inputs. Persistent activity had consistent features regardless of the initiating stimulus; it was driven by non-NMDA glutamate receptors yet consisted of an initial GABA mediated component, followed by a prolonged synaptically mediated inward current that maintained the sustained depolarization on which rode many asynchronous GABA-mediated events. The stereotyped nature of the multiple-component persistent activity pattern reported here might be a common feature of interconnected cortical networks but within PFC could be related to the persistent activity required for working memory.