Theta Rhythms Coordinate Hippocampal–Prefrontal Interactions in a Spatial Memory Task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

Theta rhythms coordinate hippocampal-prefrontal interactions in a spatial memory task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

Expectations and outcomes: decision-making in the primate brain

Success in a constantly changing environment requires that decision-making strategies be updated as reward contingencies change. How this is accomplished by the nervous system has, until recently, remained a profound mystery. New studies coupling economic theory with neurophysiological techniques have revealed the explicit representation of behavioral value. Specifically, when fluid reinforcement is paired with visually-guided eye movements, neurons in parietal cortex, prefrontal cortex, the basal ganglia, and superior colliculus—all nodes in a network linking visual stimulation with the generation of oculomotor behavior—encode the expected value of targets lying within their response fields. Other brain areas have been implicated in the processing of reward-related information in the abstract: midbrain dopaminergic neurons, for instance, signal an error in reward prediction. Still other brain areas link information about reward to the selection and performance of specific actions in order for behavior to adapt to changing environmental exigencies. Neurons in posterior cingulate cortex have been shown to carry signals related to both reward outcomes and oculomotor behavior, suggesting that they participate in updating estimates of orienting value.     

Reading hidden intentions in the human brain

When humans are engaged in goal-related processing, activity in prefrontal cortex is increased. However, it has remained unclear whether this prefrontal activity encodes a subject's current intention. Instead, increased levels of activity could reflect preparation of motor responses, holding in mind a set of potential choices, tracking the memory of previous responses, or general processes related to establishing a new task set. Here we study subjects who freely decided which of two tasks to perform and covertly held onto an intention during a variable delay. Only after this delay did they perform the chosen task and indicate which task they had prepared. We demonstrate that during the delay, it is possible to decode from activity in medial and lateral regions of prefrontal cortex which of two tasks the subjects were covertly intending to perform. This suggests that covert goals can be represented by distributed patterns of activity in the prefrontal cortex, thereby providing a potential neural substrate for prospective memory. During task execution, most information could be decoded from a more posterior region of prefrontal cortex, suggesting that different brain regions encode goals during task preparation and task execution. Decoding of intentions was most robust from the medial prefrontal cortex, which is consistent with a specific role of this region when subjects reflect on their own mental states.     

Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits

Nicotine is the principle addictive agent delivered via cigarette smoking. The addictive activity of nicotine is due to potent interactions with nicotinic acetylcholine receptors (nAChRs) on neurons in the reinforcement and reward circuits of the brain. Beyond its addictive actions, nicotine is thought to have positive effects on performance in working memory and short-term attention-related tasks. The brain areas involved in such behaviors are part of an extensive cortico-limbic network that includes relays between prefrontal cortex (PFC) and cingulate cortex (CC), hippocampus, amygdala, ventral tegmental area (VTA) and the nucleus accumbens (nAcc). Nicotine activates a broad array of nAChRs subtypes that can be targeted to pre- as well as peri- and post-synaptic locations in these areas. Thereby, nicotine not only excites different types of neurons, but it also perturbs baseline neuronal communication, alters synaptic properties and modulates synaptic plasticity.In this review we focus on recent findings on nicotinic modulation of cortical circuits and their targets fields, which show that acute and transient activation of nicotinic receptors in cortico-limbic circuits triggers a series of events that affects cognitive performance in a long lasting manner. Understanding how nicotine induces long-term changes in synapses and alters plasticity in the cortico-limbic circuits is essential to determining how these areas interact in decoding fundamental aspects of cognition and reward.     

猕猴前额皮层神经元对信号刺激和无关刺激反应的比较研究

在两只已建立视觉分辨行为以及一只未经训练的猕猴上记录了前额皮层主沟区的单位放电,视觉分辨作业包括下列事件;（1）暗示信号红光（在R模式中）或蓝光（在B模式中）（1.30^s);(2）延缓期（2.10s);（3）反应期出现白光（1.88s)在R模式中动物必需在白光出现后立即拉杆以避免电击在B模式中不给予电击,要求动物不拉杆,共记录了127个前额皮层单位,其中80个单位的放电变化与视觉分辨作业的事件相关,占总数的63%,在测试间歇期内观察了前额皮尾神经元对无关的短声\闪光以及闪烁的红、蓝和白光的反应,总共对96个单位进行了短声和/或闪光刺激的测试,其中23个（24%）对上述刺激产生反应,并大部分（15个）是与行为作业中事件相关的单位,在对103个单位进行闪烁的红、蓝、白光测试中,发现只有12个（12%）单位有反应,在另一只未经训练的猕猴的前额皮层主沟区记录了100个单位,发现只有4个（4%）单位对无关的光刺激有反应,这些光刺激的物理性与上述实验中所采用的刺激相同,以上结果表明,通过学习具有行为意义的刺激能引起更多的前额叶神经元的放电活动,也就是说前额叶神经元对具有行为意义的刺激的反应是在学习过程中形成的,它们的活动是可塑的。     

Stimulus-Response-Outcome Coding in the Pigeon Nidopallium Caudolaterale

A prerequisite for adaptive goal-directed behavior is that animals constantly evaluate action outcomes and relate them to both their antecedent behavior and to stimuli predictive of reward or non-reward. Here, we investigate whether single neurons in the avian nidopallium caudolaterale (NCL), a multimodal associative forebrain structure and a presumed analogue of mammalian prefrontal cortex, represent information useful for goal-directed behavior. We subjected pigeons to a go-nogo task, in which responding to one visual stimulus (S+) was partially reinforced, responding to another stimulus (S–) was punished, and responding to test stimuli from the same physical dimension (spatial frequency) was inconsequential. The birds responded most intensely to S+, and their response rates decreased monotonically as stimuli became progressively dissimilar to S+; thereby, response rates provided a behavioral index of reward expectancy. We found that many NCL neurons'' responses were modulated in the stimulus discrimination phase, the outcome phase, or both. A substantial fraction of neurons increased firing for cues predicting non-reward or decreased firing for cues predicting reward. Interestingly, the same neurons also responded when reward was expected but not delivered, and could thus provide a negative reward prediction error or, alternatively, signal negative value. In addition, many cells showed motor-related response modulation. In summary, NCL neurons represent information about the reward value of specific stimuli, instrumental actions as well as action outcomes, and therefore provide signals useful for adaptive behavior in dynamically changing environments.     

Distributed coding of actual and hypothetical outcomes in the orbital and dorsolateral prefrontal cortex

Knowledge about hypothetical outcomes from unchosen actions is beneficial only when such outcomes can be correctly attributed to specific actions. Here we show that during a simulated rock-paper-scissors game, rhesus monkeys can adjust their choice behaviors according to both actual and hypothetical outcomes from their chosen and unchosen actions, respectively. In addition, neurons in both dorsolateral prefrontal cortex and orbitofrontal cortex encoded the signals related to actual and hypothetical outcomes immediately after they were revealed to the animal. Moreover, compared to the neurons in the orbitofrontal cortex, those in the dorsolateral prefrontal cortex were more likely to change their activity according to the hypothetical outcomes from specific actions. Conjunctive and parallel coding of multiple actions and their outcomes in the prefrontal cortex might enhance the efficiency of reinforcement learning and also contribute to their context-dependent memory.     

Temporal evolution of a decision-making process in medial premotor cortex

The events linking sensory discrimination to motor action remain unclear. It is not known, for example, whether the motor areas of the frontal lobe receive the result of the discrimination process from other areas or whether they actively participate in it. To investigate this, we trained monkeys to discriminate between two mechanical vibrations applied sequentially to the fingertips; here subjects had to recall the first vibration, compare it to the second one, and indicate with a hand/arm movement which of the two vibrations had the higher frequency. We recorded the activity of single neurons in medial premotor cortex (MPC) and found that their responses correlate with the diverse stages of the discrimination process. Thus, activity in MPC reflects the temporal evolution of the decision-making process leading to action selection during this perceptual task.     

Representation of attended versus remembered locations in prefrontal cortex

A great deal of research on the prefrontal cortex (PF), especially in nonhuman primates, has focused on the theory that it functions predominantly in the maintenance of short-term memories, and neurophysiologists have often interpreted PF's delay-period activity in the context of this theory. Neuroimaging results, however, suggest that PF's function extends beyond the maintenance of memories to include aspects of attention, such as the monitoring and selection of information. To explore alternative interpretations of PF's delay-period activity, we investigated the discharge rates of single PF neurons as monkeys attended to a stimulus marking one location while remembering a different, unmarked location. Both locations served as potential targets of a saccadic eye movement. Although the task made intensive demands on short-term memory, the largest proportion of PF neurons represented attended locations, not remembered ones. The present findings show that short-term memory functions cannot account for all, or even most, delay-period activity in the part of PF explored. Instead, PF's delay-period activity probably contributes more to the process of attentional selection.     

Influences of rewarding and aversive outcomes on activity in macaque lateral prefrontal cortex

Both appetitive and aversive outcomes can reinforce animal behavior. It is not clear, however, whether the opposing kinds of reinforcers are processed by specific or common neural mechanisms. To investigate this issue, we studied macaque monkeys that performed a memory-guided saccade task for three different outcomes, namely delivery of liquid reward, avoidance of air puff, and feedback sound only. Animals performed the task best in rewarded trials, intermediately in aversive trials, and worst in sound-only trials. Most task-related activity in lateral prefrontal cortex was differentially influenced by the reinforcers. Aversive avoidance had clear effects on some prefrontal neurons, although the effects of rewards were more common. We also observed neurons modulated by both positive and negative reinforcers, reflecting reinforcement or attentional processes. Our results demonstrate that information about positive and negative reinforcers is processed differentially in prefrontal cortex, which could contribute to the role of this structure in goal-directed behavior.     

Learning an operant conditioning task differentially induces gliogenesis in the medial prefrontal cortex and neurogenesis in the hippocampus

Circuit modification associated with learning and memory involves multiple events, including the addition and remotion of newborn cells trough adulthood. Adult neurogenesis and gliogenesis were mainly described in models of voluntary exercise, enriched environments, spatial learning and memory task; nevertheless, it is unknown whether it is a common mechanism among different learning paradigms, like reward dependent tasks. Therefore, we evaluated cell proliferation, neurogenesis, astrogliogenesis, survival and neuronal maturation in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP) during learning an operant conditioning task. This was performed by using endogenous markers of cell proliferation, and a bromodeoxiuridine (BrdU) injection schedule in two different phases of learning. Learning an operant conditioning is divided in two phases: a first phase when animals were considered incompletely trained (IT, animals that were learning the task) when they performed between 50% and 65% of the responses, and a second phase when animals were considered trained (Tr, animals that completely learned the task) when they reached 100% of the responses with a latency time lower than 5 seconds. We found that learning an operant conditioning task promoted cell proliferation in both phases of learning in the mPFC and HIPP. Additionally, the results presented showed that astrogliogenesis was induced in the medial prefrontal cortex (mPFC) in both phases, however, the first phase promoted survival of these new born astrocytes. On the other hand, an increased number of new born immature neurons was observed in the HIPP only in the first phase of learning, whereas, decreased values were observed in the second phase. Finally, we found that neuronal maturation was induced only during the first phase. This study shows for the first time that learning a reward-dependent task, like the operant conditioning, promotes neurogenesis, astrogliogenesis, survival and neuronal maturation depending on the learning phase in the mPFC-HIPP circuit.     

Eye position influences auditory responses in primate inferior colliculus

We examined the frame of reference of auditory responses in the inferior colliculus in monkeys fixating visual stimuli at different locations. Eye position modulated the level of auditory responses in 33% of the neurons we encountered, but it did not appear to shift their spatial tuning. The effect of eye position on auditory responses was substantial-comparable in magnitude to that of sound location. The eye position signal appeared to interact with the auditory responses in at least a partly multiplicative fashion. We conclude that the representation of sound location in primate IC is distributed and that the frame of reference is intermediate between head- and eye-centered coordinates. The information contained in these neurons appears to be sufficient for later neural stages to calculate the positions of sounds with respect to the eyes.     

Competing sound sources reveal spatial effects in cortical processing

Why is spatial tuning in auditory cortex weak, even though location is important to object recognition in natural settings? This question continues to vex neuroscientists focused on linking physiological results to auditory perception. Here we show that the spatial locations of simultaneous, competing sound sources dramatically influence how well neural spike trains recorded from the zebra finch field L (an analog of mammalian primary auditory cortex) encode source identity. We find that the location of a birdsong played in quiet has little effect on the fidelity of the neural encoding of the song. However, when the song is presented along with a masker, spatial effects are pronounced. For each spatial configuration, a subset of neurons encodes song identity more robustly than others. As a result, competing sources from different locations dominate responses of different neural subpopulations, helping to separate neural responses into independent representations. These results help elucidate how cortical processing exploits spatial information to provide a substrate for selective spatial auditory attention.     

Activity in the lateral prefrontal cortex reflects multiple steps of future events in action plans

To achieve a behavioral goal in a complex environment, we must plan multiple steps of motor behavior. On planning a series of actions, we anticipate future events that will occur as a result of each action and mentally organize the temporal sequence of events. To investigate the involvement of the lateral prefrontal cortex (PFC) in such multistep planning, we examined neuronal activity in the PFC of monkeys performing a maze task that required the planning of stepwise cursor movements to reach a goal. During the preparatory period, PFC neurons reflected each of all forthcoming cursor movements, rather than arm movements. In contrast, in the primary motor cortex, most neuronal activity reflected arm movements but little of cursor movements during the preparatory period, as well as during movement execution. Our data suggest that the PFC is involved primarily in planning multiple future events that occur as a consequence of behavioral actions.     

Contribution of area MT to stereoscopic depth perception: choice-related response modulations reflect task strategy

Due to the diversity of tuning properties in sensory cortex, only a fraction of neurons are engaged in a particular task. Characterizing the tuning properties of neurons that are functionally linked to behavior is essential for understanding how activity is "read out" from sensory maps to guide decisions. We recorded from middle temporal (MT) neurons while monkeys performed a depth discrimination task, and we characterized the linkage between MT responses and behavioral choices. Trial-to-trial response fluctuations of MT neurons with odd-symmetric ("Near," "Far") disparity tuning were predictive of monkeys' choices, whereas responses of neurons with even-symmetric tuning were not. This result cannot be explained by neuronal sensitivity or any other response property of MT neurons that we examined but is simply explained by the task strategy that monkeys learned during training. We suggest that this approach provides a physiological means to explore how task strategies are implemented in the brain.     

The role of the rat medial prefrontal cortex in adapting to changes in instrumental contingency

In order to select actions appropriate to current needs, a subject must identify relationships between actions and events. Control over the environment is determined by the degree to which action consequences can be predicted, as described by action-outcome contingencies--i.e. performing an action should affect the probability of the outcome. We evaluated in a first experiment adaptation to contingency changes in rats with neurotoxic lesions of the medial prefrontal cortex. Results indicate that this brain region is not critical to adjust instrumental responding to a negative contingency where the rats must refrain from pressing a lever, as this action prevents reward delivery. By contrast, this brain region is required to reduce responding in a non-contingent situation where the same number of rewards is freely delivered and actions do not affect the outcome any more. In a second experiment, we determined that this effect does not result from a different perception of temporal relationships between actions and outcomes since lesioned rats adapted normally to gradually increasing delays in reward delivery. These data indicate that the medial prefrontal cortex is not directly involved in evaluating the correlation between action--and reward--rates or in the perception of reward delays. The deficit in lesioned rats appears to consist of an abnormal response to the balance between contingent and non-contingent rewards. By highlighting the role of prefrontal regions in adapting to the causal status of actions, these data contribute to our understanding of the neural basis of choice tasks.     

Robust spatial working memory through homeostatic synaptic scaling in heterogeneous cortical networks

The concept of bell-shaped persistent neural activity represents a cornerstone of the theory for the internal representation of analog quantities, such as spatial location or head direction. Previous models, however, relied on the unrealistic assumption of network homogeneity. We investigate this issue in a network model where fine tuning of parameters is destroyed by heterogeneities in cellular and synaptic properties. Heterogeneities result in the loss of stored spatial information in a few seconds. Accurate encoding is recovered when a homeostatic mechanism scales the excitatory synapses to each cell to compensate for the heterogeneity in cellular excitability and synaptic inputs. Moreover, the more realistic model produces a wide diversity of tuning curves, as commonly observed in recordings from prefrontal neurons. We conclude that recurrent attractor networks in conjunction with appropriate homeostatic mechanisms provide a robust, biologically plausible theoretical framework for understanding the neural circuit basis of spatial working memory.     

Dynamics of population code for working memory in the prefrontal cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.     

Spatial learning and action planning in a prefrontal cortical network model

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive "insight" capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.