Hippocampal and medial prefrontal ensemble spiking represents episodes and rules in similar task spaces.

Episodic memory requires the hippocampus and prefrontal cortex to guide decisions by representing events in spatial, temporal, and personal contexts. Both brain regions have been described by cognitive theories that represent events in context as locations in maps or memory spaces. We query whether ensemble spiking in these regions described spatial structures as rats performed memory tasks. From each ensemble, we construct a state-space with each point defined by the coordinated spiking of single and pairs of units in 125-ms bins and investigate how state-space locations discriminate task features. Trajectories through state-spaces correspond with behavioral episodes framed by spatial, temporal, and internal contexts. Both hippocampal and prefrontal ensembles distinguish maze locations, task intervals, and goals by distances between state-space locations, consistent with cognitive mapping and relational memory space theories of episodic memory. Prefrontal modulation of hippocampal activity may guide choices by directing memory representations toward appropriate state-space goal locations.

Hippocampal and Medial Prefrontal Cortex Fractal Spiking Patterns Encode Episodes and Rules.

A central question in neuroscience is how the brain represents and processes information to guide behavior. The principles that organize brain computations are not fully known, and could include scale-free, or fractal patterns of neuronal activity. Scale-free brain activity may be a natural consequence of the relatively small subsets of neuronal populations that respond to task features, i.e., sparse coding. The size of the active subsets constrains the possible sequences of inter-spike intervals (ISI), and selecting from this limited set may produce firing patterns across wide-ranging timescales that form fractal spiking patterns. To investigate the extent to which fractal spiking patterns corresponded with task features, we analyzed ISIs in simultaneously recorded populations of CA1 and medial prefrontal cortical (mPFC) neurons in rats performing a spatial memory task that required both structures. CA1 and mPFC ISI sequences formed fractal patterns that predicted memory performance. CA1 pattern duration, but not length or content, varied with learning speed and memory performance whereas mPFC patterns did not. The most common CA1 and mPFC patterns corresponded with each region's cognitive function: CA1 patterns encoded behavioral episodes which linked the start, choice, and goal of paths through the maze whereas mPFC patterns encoded behavioral "rules" which guided goal selection. mPFC patterns predicted changing CA1 spike patterns only as animals learned new rules. Together, the results suggest that CA1 and mPFC population activity may predict choice outcomes by using fractal ISI patterns to compute task features.

Goal Choices Modify Frontotemporal Memory Representations.

Adapting flexibly to changing circumstances is guided by memory of past choices, their outcomes in similar circumstances, and a method for choosing among potential actions. The hippocampus (HPC) is needed to remember episodes, and the prefrontal cortex (PFC) helps guide memory retrieval. Single-unit activity in the HPC and PFC correlates with such cognitive functions. Previous work recorded CA1 and mPFC activity as male rats performed a spatial reversal task in a plus maze that requires both structures, found that PFC activity helps reactivate HPC representations of pending goal choices but did not describe frontotemporal interactions after choices. We describe these interactions after choices here. CA1 activity tracked both current goal location and the past starting location of single trials; PFC activity tracked current goal location better than past start location. CA1 and PFC reciprocally modulated representations of each other both before and after goal choices. After choices, CA1 activity predicted changes in PFC activity in subsequent trials, and the magnitude of this prediction correlated with faster learning. In contrast, PFC start arm activity more strongly modulated CA1 activity after choices correlated with slower learning. Together, the results suggest post-choice HPC activity conveys retrospective signals to the PFC, which combines different paths to common goals into rules. In subsequent trials, prechoice mPFC activity modulates prospective CA1 signals informing goal selection.SIGNIFICANCE STATEMENT HPC and PFC activity supports cognitive flexibility in changing circumstances. HPC signals represent behavioral episodes that link the start, choice, and goal of paths. PFC signals represent rules that guide goal-directed actions. Although prior studies described HPC-PFC interactions preceding decisions in the plus maze, post-decision interactions were not investigated. Here, we show post-choice HPC and PFC activity distinguished the start and goal of paths, and CA1 signaled the past start of each trial more accurately than mPFC. Postchoice CA1 activity modulated subsequent PFC activity, so rewarded actions were more likely to occur. Together, the results show that in changing circumstances, HPC retrospective codes modulate subsequent PFC coding, which in turn modulates HPC prospective codes that predict choices.

Hippocampal signals modify orbitofrontal representations to learn new paths.

We often remember the consequences of past choices to adapt to changing circumstances. Recalling past events requires the hippocampus (HPC), and using stimuli to anticipate outcome values requires the orbitofrontal cortex (OFC).1-3 Spatial reversal tasks require both structures to navigate newly rewarded paths.4,5 Both HPC place6 and OFC value cells7,8 fire in phase with theta (4-12 Hz) oscillations. Both structures are described as cognitive maps: HPC maps space9 and OFC maps task states.10 These similarities imply that OFC-HPC interactions are crucial for using memory to predict outcomes when circumstances change, but the mechanisms remain largely unknown. To investigate possible interactions, we simultaneously recorded ensembles in OFC and CA1 as rats learned spatial reversals in a plus maze. Striking interactions occurred only while rats learned their first reversal: CA1 population vectors predicted changes in OFC activity but not vice versa, OFC spikes phase locked to hippocampal theta oscillations, mixed pairs of CA1 and OFC neurons fired together within single theta cycles, and CA1 led OFC spikes by ∼30 ms. After the new contingency became familiar, CA1 ensembles stably represented distinct spatial paths, whereas OFC ensembles developed more generalized goal arm representations in different paths to identical rewards. These frontotemporal interactions, engaged selectively when new task features inform decision-making, suggest a mechanism for linking novel episodes with expected outcomes, when HPC signals trigger "cognitive remapping" by OFC.11.

An in silico model for determining the influence of neuronal co-activity on rodent spatial behavior.

BACKGROUND: Neuropsychological and neurophysiological analyses focus on understanding how neuronal activity and co-activity predict behavior. Experimental techniques allow for modulation of neuronal activity, but do not control neuronal ensemble spatiotemporal firing patterns, and there are few, if any, sophisticated in silico techniques which accurately reconstruct physiological neural spike trains and behavior using unit co-activity as an input parameter. NEW METHOD: Our approach to simulation of neuronal spike trains is based on using state space modeling to estimate a weighted graph of interaction strengths between pairs of neurons along with separate estimations of spiking threshold voltage and neuronal membrane leakage. These parameters allow us to tune a biophysical model which is then employed to accurately reconstruct spike trains from freely behaving animals and then use these spike trains to estimate an animal's spatial behavior. The reconstructed spatial behavior allows us to confirm the same information is present in both the recorded and simulated spike trains. RESULTS: Our method reconstructs spike trains (98 ± 0.0013% like original spike trains, mean ± SEM) and animal position (9.468 ± 0.240 cm, mean ± SEM) with high fidelity. COMPARISON WITH EXISTING METHOD(S): To our knowledge, this is the first method that uses empirically derived network connectivity to constrain biophysical parameters and predict spatial behavior. Together, these methods allow in silico quantification of the contribution of specific unit activity and co-activity to animal spatial behavior. CONCLUSIONS: Our novel approach provides a flexible, robust in silico technique for determining the contribution of specific neuronal activity and co-activity to spatial behavior.

Medial Prefrontal Cortex Reduces Memory Interference by Modifying Hippocampal Encoding.

The prefrontal cortex (PFC) is crucial for accurate memory performance when prior knowledge interferes with new learning, but the mechanisms that minimize proactive interference are unknown. To investigate these, we assessed the influence of medial PFC (mPFC) activity on spatial learning and hippocampal coding in a plus maze task that requires both structures. mPFC inactivation did not impair spatial learning or retrieval per se, but impaired the ability to follow changing spatial rules. mPFC and CA1 ensembles recorded simultaneously predicted goal choices and tracked changing rules; inactivating mPFC attenuated CA1 prospective coding. mPFC activity modified CA1 codes during learning, which in turn predicted how quickly rats adapted to subsequent rule changes. The results suggest that task rules signaled by the mPFC become incorporated into hippocampal representations and support prospective coding. By this mechanism, mPFC activity prevents interference by "teaching" the hippocampus to retrieve distinct representations of similar circumstances.

Basal forebrain projections to the lateral habenula modulate aggression reward.

Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward.

The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.

Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress.

Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.

Involvement of the anterior cingulate and frontoinsular cortices in rapid processing of salient facial emotional information.

The anterior cingulate cortex (ACC) and frontoinsular cortex (FI) have been implicated in processing information across a variety of domains, including those related to attention and emotion. However, their role in rapid information processing, for example, as required for timely processing of salient stimuli, is not well understood. Here, we designed an emotional face priming paradigm and employed functional magnetic resonance imaging to elucidate their role in these mechanisms. Target faces with either neutral or fearful emotion were briefly primed by either neutral or fearful faces, or by blank ovals. The pregenual ACC and the FI, together with other regions, such as the amygdala, were preferentially activated in response to fearful face priming, suggesting that these regions are involved in the rapid processing of salient facial emotional information.

Genetics as a tool for the dissociation of mental operations over the course of development.

In recent years it has become possible to differentiate separable aspects of attention and to characterize the anatomical structure and dynamic states of their underlying networks. When individual differences in the structure and dynamics of these networks are used as dependent measures in associations with individual genetic variation, it becomes possible to assign cellular and molecular changes that occur over the course of normal development to specific aspects of network structure and function. In this way, a more granular understanding of the physiology of neural networks can be obtained. Here we review a translational research strategy focused on how genetic variation contributes to the normal development of attentional function. We seek to use genetic information to help construct a multinode, multinetwork model that can explain, in part, individual differences in the development of attention over the course of development.

Neural correlates of using distancing to regulate emotional responses to social situations.

Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one's self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.

Functional dissociation of the frontoinsular and anterior cingulate cortices in empathy for pain.

The frontoinsular cortex (FI) and the anterior cingulate cortex (ACC) are thought to be involved in empathy for others' pain. However, the functional roles of FI and ACC in empathetic responses have not yet been clearly dissociated in previous studies. In this study, participants viewed color photographs depicting human body parts in painful or nonpainful situations and performed either pain judgment (painful/nonpainful) or laterality judgment (left/right) of the body parts. We found that activation of FI, rather than ACC, showed significant increase for painful compared with nonpainful images, regardless of the task requirement. Our data suggest a clear functional dissociation between FI and ACC in which FI is more domain-specific than ACC when processing empathy for pain.

Effective connectivity of the fronto-parietal network during attentional control.

The ACC, the dorsolateral prefrontal cortex (DLPFC), and the parietal cortex near/along the intraparietal sulcus (IPS) are members of a network subserving attentional control. Our recent study revealed that these regions participate in both response anticipation and conflict processing. However, little is known about the relative contribution of these regions in attentional control and how the dynamic interactions among these regions are modulated by detection of predicted versus unpredicted targets and conflict processing. Here, we examined effective connectivity using dynamic causal modeling among these three regions during a flanker task with or without a target onset cue. We compared various models in which different connections among ACC, DLPFC, and IPS were modulated by bottom-up stimulus-driven surprise and top-down conflict processing using Bayesian model selection procedures. The most optimal of these models incorporated contextual modulation that allowed processing of unexpected (surprising) targets to mediate the influence of the IPS over ACC and DLPFC and conflict processing to mediate the influence of ACC and DLPFC over the IPS. This result suggests that the IPS plays an initiative role in this network in the processing of surprise targets, whereas ACC and DLPFC interact with each other to resolve conflict through attentional modulation implemented via the IPS.

Neural correlates of the use of psychological distancing to regulate responses to negative social cues: a study of patients with borderline personality disorder.

BACKGROUND: Emotional instability is a defining feature of borderline personality disorder (BPD); yet, little is understood about its underlying neural correlates. One possible contributing factor to emotional instability is a failure to adequately employ adaptive cognitive regulatory strategies such as psychological distancing. METHODS: To determine whether there are differences in neural dynamics underlying this control strategy between BPD patients and healthy control (HC) subjects, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging signals were acquired as 18 BPD and 16 HC subjects distanced from or simply looked at pictures depicting social interactions. Contrasts in signal between distance and look conditions were compared between groups. RESULTS: Borderline personality disorder patients showed a different pattern of activation compared with HC subjects when looking at negative versus neutral pictures. When distancing versus looking at negative pictures, both groups showed decreased negative affect ratings and increased activation of the dorsolateral prefrontal cortex, areas near/along the intraparietal sulcus (IPS), ventrolateral prefrontal cortex, and posterior cingulate/precuneus regions. However, the BPD group showed less BOLD signal change in dorsal anterior cingulate cortex and IPS, less deactivation in the amygdala, and greater activation in the superior temporal sulcus and superior frontal gyrus. CONCLUSIONS: Borderline personality disorder and HC subjects display different neural dynamics while passively viewing social emotional stimuli. In addition, BPD patients do not engage the cognitive control regions to the extent that HCs do when employing a distancing strategy to regulate emotional reactions, which may be a factor contributing to the affective instability of BPD.

A functional magnetic resonance imaging study of deliberate emotion regulation in resilience and posttraumatic stress disorder.

BACKGROUND: Sexual violence is an important public health problem in the United States, with 13% to 26% of women reporting a history of sexual assault. While unfortunately common, there is substantial individual variability in response to sexual assault. Approximately half of rape victims develop posttraumatic stress disorder (PTSD), while others develop no psychopathology (e.g., trauma-exposed non-PTSD). In this project, we examined the neural mechanisms underlying differences in response to sexual violence, focusing specifically on the deliberate modification of emotional responses to negative stimuli. METHODS: Using functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent (BOLD) response, we examined the neural circuitry underlying effortful modification of emotional responses to negative pictures in 42 women: 14 with PTSD after sexual trauma, 14 with no psychiatric diagnosis after sexual trauma, and 14 nontraumatized control subjects. RESULTS: In response to deliberate attempts to downregulate emotional responses, nontraumatized healthy control subjects were more successful than either trauma-exposed group (PTSD or non-PTSD) in downregulating responses to the negative pictures as measured by subjective rating and BOLD response in regions of prefrontal cortex (PFC). In contrast, after deliberate attempts to upregulate emotional responses, regions of PFC were activated by trauma-exposed non-PTSD subjects more than by healthy control subjects or PTSD subjects. CONCLUSIONS: Successful downregulation of emotional responses to negative stimuli appears to be impaired by trauma exposure. In contrast, the ability to upregulate emotional responses to negative stimuli may be a protective factor in the face of trauma exposure and associated with resilience.

Testing the behavioral interaction and integration of attentional networks.

One current conceptualization of attention subdivides it into functions of alerting, orienting, and executive control. Alerting describes the function of tonically maintaining the alert state and phasically responding to a warning signal. Automatic and voluntary orienting are involved in the selection of information among multiple sensory inputs. Executive control describes a set of more complex operations that include detecting and resolving conflicts in order to control thoughts or behaviors. Converging evidence supports this theory of attention by showing that each function appears to be subserved by anatomically distinct networks in the brain and differentially innervated by various neuromodulatory systems. Although much research has been dedicated to understanding the functional separation of these networks in both healthy and disease states, the interaction and integration among these networks still remain unclear. In this study, we aimed to characterize possible behavioral interaction and integration in healthy adult volunteers using a revised attention network test (ANT-R) with cue-target interval and cue validity manipulations. We found that whereas alerting improves overall response speed, it exerts negative influence on executive control under certain conditions. A valid orienting cue enhances but an invalid cue diminishes the ability of executive control to overcome conflict. The results support the hypothesis of functional integration and interaction of these brain networks.

Alexithymic trait and voluntary control in healthy adults.

BACKGROUND: Alexithymia is a personality trait characterized by deficiency in understanding, processing, or describing emotions. Recent studies have revealed that alexithymia is associated with less activation of the anterior cingulate cortex, a brain region shown to play a role in cognitive and emotional processing. However, few studies have directly investigated the cognitive domain in relation to alexithymia to examine whether alexithymic trait is related to less efficient voluntary control. METHODOLOGY/PRINCIPAL FINDINGS: We examined the relationship between alexithymic trait and voluntary control in a group of healthy volunteers. We used the 20-item Toronto Alexithymia Scale (TAS-20) to measure alexithymic trait. Additionally, we examined state and trait voluntary control using the revised Attention Network Test (ANT-R) and the Adult Temperament Questionnaire (ATQ), respectively. Alexithymic trait was positively correlated with the overall reaction time of the ANT-R, and negatively correlated with the Effortful Control factor of the ATQ. CONCLUSIONS/SIGNIFICANCE: Our results suggest that alexithymic trait is associated with less efficient voluntary control.

Searching for the majority: algorithms of voluntary control.

Voluntary control of information processing is crucial to allocate resources and prioritize the processes that are most important under a given situation; the algorithms underlying such control, however, are often not clear. We investigated possible algorithms of control for the performance of the majority function, in which participants searched for and identified one of two alternative categories (left or right pointing arrows) as composing the majority in each stimulus set. We manipulated the amount (set size of 1, 3, and 5) and content (ratio of left and right pointing arrows within a set) of the inputs to test competing hypotheses regarding mental operations for information processing. Using a novel measure based on computational load, we found that reaction time was best predicted by a grouping search algorithm as compared to alternative algorithms (i.e., exhaustive or self-terminating search). The grouping search algorithm involves sampling and resampling of the inputs before a decision is reached. These findings highlight the importance of investigating the implications of voluntary control via algorithms of mental operations.

Functional connectivity of the sensorimotor area in naturally sleeping infants.

Patterns of cortical functional connectivity in normal infants were examined during natural sleep by observing the time course of very low frequency oscillations. Such oscillations represent fluctuations in blood oxygenation level and cortical blood flow thus allowing computation of neurophysiologic connectivity. Structural and resting-state information were acquired for 11 infants, with a mean age of 12.8 months, using a GE 1.5 T MR scanner. Resting-state data were processed and significant functional connectivity within the sensorimotor area was identified using independent component analysis. Unilateral functional connectivity in the developing sensory-motor cortices was observed. Power spectral analysis showed that slow frequency oscillations dominated the hemodynamic signal at this age, with, on average, a peak frequency for all subjects of 0.02 Hz. Our data suggest that there is more intrahemispheric than interhemispheric connectivity in the sensorimotor area of naturally sleeping infants. This non-invasive imaging technique, developed to allow reliable scanning of normal infants without sedation, enabled computation of neurophysiologic connectivity for the first time in naturally sleeping infants. Such techniques permit elucidation of the role of slow cortical oscillations during early brain development and may reveal critical information regarding the normative development and lateralization of brain networks across time.