Basal forebrain and prelimbic cortex connectivity is related to behavioral response in an attention task.

The basal forebrain (BF) is critical for the motivational recruitment of attention in response to reward-related cues. This finding is consistent with a role for the BF in encoding and transmitting motivational salience and readying prefrontal circuits for further attentional processing. We recorded local field potentials to determine connectivity between prelimbic cortex (PrL) and BF during the modulation of attention by reward-related cues. We find that theta and gamma power are robustly associated with behavior. Power in both bands is significantly lower during trials in which an incorrect behavioral response is made. We find strong coherence during responses that are significantly stronger when a correct response is made. We show that information flow is largely monodirectional from BF to and is strongest when correct responses are made. These experiments demonstrate that connectivity between BF and the PrL increases during periods of increased motivational recruitment of attentional resources.

Utilizing synthetic training data for the supervised classification of rat ultrasonic vocalizations.

Murine rodents generate ultrasonic vocalizations (USVs) with frequencies that extend to around 120 kHz. These calls are important in social behaviour, and so their analysis can provide insights into the function of vocal communication, and its dysfunction. The manual identification of USVs, and subsequent classification into different subcategories is time consuming. Although machine learning approaches for identification and classification can lead to enormous efficiency gains, the time and effort required to generate training data can be high, and the accuracy of current approaches can be problematic. Here, we compare the detection and classification performance of a trained human against two convolutional neural networks (CNNs), DeepSqueak (DS) and VocalMat (VM), on audio containing rat USVs. Furthermore, we test the effect of inserting synthetic USVs into the training data of the VM CNN as a means of reducing the workload associated with generating a training set. Our results indicate that VM outperformed the DS CNN on measures of call identification, and classification. Additionally, we found that the augmentation of training data with synthetic images resulted in a further improvement in accuracy, such that it was sufficiently close to human performance to allow for the use of this software in laboratory conditions.

Hippocampal phase precession is preserved under ketamine, but the range of precession across a theta cycle is reduced.

BACKGROUND: Hippocampal phase precession, which depends on the precise spike timing of place cells relative to local theta oscillations, has been proposed to underlie sequential memory. N-methyl-D-asparate (NMDA) receptor antagonists such as ketamine disrupt memory and also reproduce several schizophrenia-like symptoms, including spatial memory impairments and disorganized cognition. It is possible that these impairments result from disruptions to phase precession. AIMS/METHODS: We used an ABA design to test whether an acute, subanesthetic dose (7.5 mg/kg) of ketamine disrupted phase precession in CA1 of male rats as they navigated around a rectangular track for a food reward. RESULTS/OUTCOMES: Ketamine did not affect the ability of CA1 place cells to precess despite changes to place cell firing rates, local field potential properties and locomotor speed. However, ketamine reduced the range of phase precession that occurred across a theta cycle. CONCLUSION: Phase precession is largely robust to acute NMDA receptor antagonism by ketamine, but the reduced range of precession could have important implications for learning and memory.

No evidence that acute clozapine administration alters CA1 phase precession in rats.

Hippocampal phase precession, wherein there is a systematic shift in the phase of neural firing against the underlying theta activity, is proposed to play an important role in the sequencing of information in memory. Previous research shows that the starting phase of precession is more variable in rats following maternal immune activation (MIA), a known risk factor for schizophrenia. Since starting phase variability has the potential to disorganize the construction of sequences of information, we tested whether the atypical antipsychotic clozapine, which ameliorates some cognitive deficits in schizophrenia, alters this aspect of phase precession. Either saline or clozapine (5 mg/kg) was administered to rats and then CA1 place cell activity was recorded from the CA1 region of the hippocampus as the animals ran around a rectangular track for food reward. When compared to saline trials, acute administration of clozapine did not affect any place cell properties, including those related to phase precession, in either control or MIA animals. Clozapine did, however, produce a reduction in locomotion speed, indicating that its presence had some effect on behaviour. These results help to constrain explanations of phase precession mechanisms and their potential role in sequence learning deficits.

Disrupted hippocampal synchrony following maternal immune activation in a rat model.

Maternal immune activation (MIA) is a risk factor for schizophrenia and other neurodevelopmental disorders. MIA in rats models a number of the brain and behavioral changes that are observed in schizophrenia, including impaired memory. Recent studies in the MIA model have shown that the firing of the hippocampal place cells that are involved in memory processes appear relatively normal, but with abnormalities in the temporal ordering of firing. In this study, we re-analyzed data from prior hippocampal electrophysiological recordings of MIA and control animals to determine whether temporal dysfunction was evident. We find that there is a decreased ratio of slow to fast gamma power, resulting from an increase in fast gamma power and a tendency toward reduced slow gamma power in MIA rats. Moreover, we observe a robust reduction in spectral coherence between hippocampal theta and both fast and slow gamma rhythms, as well as changes in the phase of theta at which fast gamma occurs. We also find the phasic organization of place cell phase precession on the theta wave to be abnormal in MIA rats. Lastly, we observe that the local field potential of MIA rats contains more frequent sharp-wave ripple events, and that place cells were more likely to fire spikes during ripples in these animals than control. These findings provide further evidence of desynchrony in MIA animals and may point to circuit-level changes that underlie failures to integrate and encode information in schizophrenia.

Maladaptive explore/exploit trade-offs in schizophrenia.

Schizophrenia is a complex disorder that remains poorly understood, particularly at the systems level. In this opinion article we argue that the explore/exploit trade-off concept provides a holistic and ecologically valid framework to resolve some of the apparent paradoxes that have emerged within schizophrenia research. We review recent evidence suggesting that fundamental explore/exploit behaviors may be maladaptive in schizophrenia during physical, visual, and cognitive foraging. We also describe how theories from the broader optimal foraging literature, such as the marginal value theorem (MVT), could provide valuable insight into how aberrant processing of reward, context, and cost/effort evaluations interact to produce maladaptive responses.

Aberrant Phase Precession of Lateral Septal Cells in a Maternal Immune Activation Model of Schizophrenia Risk May Disrupt the Integration of Location with Reward.

Spatial memory and reward processing are known to be disrupted in schizophrenia. Since the lateral septum (LS) may play an important role in the integration of location and reward, we examined the effect of maternal immune activation (MIA), a known schizophrenia risk factor, on spatial representation in the rat LS. In support of a previous study, we found that spatial location is represented as a phase code in the rostral LS of adult male rats, so that LS cell spiking shifts systematically against the phase of the hippocampal, theta-frequency, local field potential as an animal moves along a track toward a reward (phase precession). Whereas shallow precession slopes were observed in control group cells, they were steeper in the MIA animals, such that firing frequently precessed across several theta cycles as the animal moved along the length of the apparatus, with subsequent ambiguity in the phase representation of location. Furthermore, an analysis of the phase trajectories of the control group cells revealed that the population tended to converge toward a common firing phase as the animal approached the reward location. This suggested that phase coding in these cells might signal both reward location and the distance to reward. By comparison, the degree of phase convergence in the MIA-group cells was weak, and the region of peak convergence was distal to the reward location. These findings suggest that a schizophrenia risk factor disrupts the phase-based encoding of location-reward relationships in the LS, potentially smearing reward representations across space.SIGNIFICANCE STATEMENT It is unclear how spatial or contextual information generated by hippocampal cells is converted to a code that can be used to signal reward location in regions, such as the VTA. Here we provide evidence that the firing phase of cells in the lateral septum, a region that links the two areas, may code reward location in the firing phase of cells. This phase coding is disrupted in a maternal immune activation model of schizophrenia risk such that representations of reward may be smeared across space in maternal immune activation animals. This could potentially underlie erroneous reward processing and misattribution of salience in schizophrenia.

Disorganization of Oscillatory Activity in Animal Models of Schizophrenia.

Schizophrenia is a chronic, debilitating disorder with diverse symptomatology, including disorganized cognition and behavior. Despite considerable research effort, we have only a limited understanding of the underlying brain dysfunction. In this article, we review the potential role of oscillatory circuits in the disorder with a particular focus on the hippocampus, a region that encodes sequential information across time and space, as well as the frontal cortex. Several mechanistic explanations of schizophrenia propose that a loss of oscillatory synchrony between and within these brain regions may underlie some of the symptoms of the disorder. We describe how these oscillations are affected in several animal models of schizophrenia, including models of genetic risk, maternal immune activation (MIA) models, and models of NMDA receptor hypofunction. We then critically discuss the evidence for disorganized oscillatory activity in these models, with a focus on gamma, sharp wave ripple, and theta activity, including the role of cross-frequency coupling as a synchronizing mechanism. Finally, we focus on phase precession, which is an oscillatory phenomenon whereby individual hippocampal place cells systematically advance their firing phase against the background theta oscillation. Phase precession is important because it allows sequential experience to be compressed into a single 120 ms theta cycle (known as a 'theta sequence'). This time window is appropriate for the induction of synaptic plasticity. We describe how disruption of phase precession could disorganize sequential processing, and thereby disrupt the ordered storage of information. A similar dysfunction in schizophrenia may contribute to cognitive symptoms, including deficits in episodic memory, working memory, and future planning.

Maternal immune activation alters the sequential structure of ultrasonic communications in male rats.

Maternal immune activation (MIA) is a risk factor for schizophrenia and many of the symptoms and neurodevelopmental changes associated with this disorder have been modelled in the rodent. While several previous studies have reported that rodent ultrasonic vocalizations (USVs) are affected by MIA, no previous study has examined whether MIA affects the way that individual USVs occur over time to produce vocalisation sequences. The sequential aspect of this behaviour may be particularly important because changes in sequencing mechanisms have been proposed as a core deficit in schizophrenia. The present research generates MIA with POLY I:C administered to pregnant Sprague-Dawley rat dams at GD15. Male pairs of MIA adult offspring or pairs of their saline controls were placed into a two-chamber apparatus where they were separated from each other by a perforated plexiglass barrier. USVs were recorded for a period of 10 â€‹min and automated detection and call review were used to classify short call types in the nominal 50 â€‹kHz band of social affiliative calls. Our data show that the duration of these 50-kHz USVs is longer in MIA rat pairs and the time between calls is shorter. Furthermore, the transition probability between call pairs was different in the MIA animals compared to the control group, indicating alterations in sequential behaviour. These results provide the first evidence that USV call sequencing is altered by the MIA intervention and suggest that further investigations of these temporally extended aspects of USV production are likely to reveal useful information about the mechanisms that underlie sequence generation. This is particularly important given previous research suggesting that sequencing deficits may have a significant impact on both behaviour and cognition.

A schizophrenia risk factor induces marked anatomical deficits at GABAergic-dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies.

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase-immunogold double labeling, three-dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3-month-old and 14-month-old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long-term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA-dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long-term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum-targeted antipsychotic drugs.

Hippocampal Sequencing Mechanisms Are Disrupted in a Maternal Immune Activation Model of Schizophrenia Risk.

Episodic memory requires information to be stored and recalled in sequential order, and these processes are disrupted in schizophrenia. Hippocampal phase precession and theta sequences are thought to provide a biological mechanism for sequential ordering of experience at timescales suitable for plasticity. These phenomena have not previously been examined in any models of schizophrenia risk. Here, we examine these phenomena in a maternal immune activation (MIA) rodent model. We show that while individual pyramidal cells in the CA1 region continue to precess normally in MIA animals, the starting phase of precession as an animal enters a new place field is considerably more variable in MIA animals than in controls. A critical consequence of this change is a disorganization of the ordered representation of experience via theta sequences. These results provide the first evidence of a biological-level mechanism that, if it occurs in schizophrenia, may explain aspects of disorganized sequential processing that contribute to the cognitive symptoms of the disorder.SIGNIFICANCE STATEMENT Hippocampal phase precession and theta sequences have been proposed as biophysical mechanisms by which the sequential structure of cognition might be ordered. Disturbances of sequential processing have frequently been observed in schizophrenia. Here, we show for the first time that phase precession and theta sequences are disrupted in a maternal immune activation (MIA) model of schizophrenia risk. This is a result of greater variability in the starting phase of precession, indicating that the mechanisms that coordinate precession at the assembly level are disrupted. We propose that this disturbance in phase precession underlies some of the disorganized cognitive symptoms that occur in schizophrenia. These findings could have important preclinical significance for the identification and treatment of schizophrenia risk factors.

Neural Markers of Event Boundaries.

The continuous flow of sensorimotor experience is segmented into events that are stored in memory as discrete representations. These events are subsequently available for reconstruction into episodic memories or to be recombined for future thinking, prediction and imagination. Here we briefly review the patterns of brain activity that accompany the processing of events, and the transitions between them, with an aim to identifying signals that would serve as event boundary markers (EBMs). Since many previous studies have highlighted a role for the hippocampus in episodic memory function, consolidation and future thinking, we focus on activity in this region. In particular, we describe the brief bursts of hippocampal activity known as sharp-wave ripples (SWRs), which tend to occur following the cessation of units of behavior, making them putative EBM candidates. While most current models of SWR function tend to focus on a potential role in memory consolidation or preplay linked to future thinking, here we consider an interpretation that incorporates an EBM component.

Hippocampal coding of conspecific position.

Many previous studies have shown that hippocampal place cells respond to the spatial position of the animal itself. Several recent studies have shown that place cells in an observer animal can also encode the location of a conspecific. The interpretation of these previous studies is, however, compromised by the fact that the observer animal was required to complete a movement that was either a duplication of the others trajectory, or a modification of it. This raises the possibility that the observed representation of the other, may have instead been a plan for the self. To test for a representation of a conspecific in a task where immediate behaviour was not immediately required of the observer, Sprague-Dawley rats were trained to run the length of a shuttle box for a food reward. They then observed a second animal (the runner) performing the same task. Positional data was obtained from the runner, while hippocampal single unit data was collected from the observer. Hippocampal single units were observed to have only limited, low resolution, firing rate-modulated representations of the runner animal. There was also evidence of a weak relationship between place cell spatial firing representations of the self and other. Some above-chance evidence of phase-coding of the runner's position was also observed in the observer animals, with an observer-centred reference frame. These results indicate that hippocampal place cells encode some limited spatial information about others when the observer's subsequent behaviour is not dependent on that of the observed.

Communication between the Anterior Cingulate Cortex and Ventral Tegmental Area during a Cost-Benefit Reversal Task.

The anterior cingulate cortex (ACC) is implicated in value-based decision making, anticipation, and adaptation; however, how ACC activity modulates these behaviors is unclear. One possibility is via the ACC's connections with the ventral tegmental area (VTA), a dopaminergic region implicated in motivation and feedback processing. We tested this by monitoring ACC and VTA local field potentials in rats performing a cost-benefit reversal task that elicited both value-based and anticipatory choices. Partial directed coherence analyses revealed that elevated 4-Hz ACC-to-VTA signaling accompanied decisions that appeared to be anticipatory. ACC-to-VTA signaling also occurred post-reversal, consistent with it being involved in the initiation of non-default behavior. An analysis of 4-Hz signals in the other direction (VTA-to-ACC) revealed that it was elevated when the rats committed errors and that this signal was followed by behavioral adaptation. Together, these findings suggest that bidirectional communication between the ACC and VTA supports behavioral flexibility.

Anterior cingulate cortex encoding of effortful behavior.

An animal's ability to assess the value of their behaviors to minimize energy use while maximizing goal achievement is critical to its survival. The anterior cingulate cortex (ACC) has been previously shown to play a critical role in this behavioral optimization process, especially when animals are faced with effortful behaviors. In the present study, we designed a novel task to investigate the role of the ACC in evaluating behaviors that varied in effort but all resulted in the same outcome. We recorded single unit activity from the ACC as rats ran back and forth in a shuttle box that could be tilted to different tilt angles (0, 15, and 25°) to manipulate effort. Overall, a majority of ACC neurons showed selective firing to specific effort conditions. During effort expenditure, ACC units showed a consistent firing rate bias toward the downhill route compared with the more difficult uphill route, regardless of the tilt angle of the apparatus. Once rats completed a run and received their fixed reward, ACC units also showed a clear firing rate preference for the single condition with the highest relative value (25° downhill). To assess effort preferences, we used a choice version of our task and confirmed that rats prefer downhill routes to uphill routes when given the choice. Overall, these results help to elucidate the functional role of the ACC in monitoring and evaluating effortful behaviors that may then bias decision-making toward behaviors with the highest utility. NEW & NOTEWORTHY We developed a novel effort paradigm to investigate how the anterior cingulate cortex (ACC) responds to behaviors with varied degrees of physical effort and how changes in effort influence the ACC's evaluation of behavioral outcomes. Our results provide evidence for a wider role of the ACC in its ability to motivate effortful behaviors and evaluate the outcome of multiple behaviors within an environment.

Reversal learning impairments in the maternal immune activation rat model of schizophrenia.

One of the cognitive symptoms observed in schizophrenia is decreased flexibility in several tasks, including reversal learning. Reversal learning has previously been tested in rats following maternal immune activation (MIA), a risk factor for schizophrenia, with varying results. Whereas some previous studies have shown that MIA rats are slower to learn a reversal, others have reported more rapid learning compared with controls. Several of these latter studies have, however, used a T-maze task with aversive, negative reinforcement as a motivating factor. Because most human studies use positive reinforcement in reversal tasks, here we tested whether reinforcement valence might be a critical factor. We ran male MIA and control rats in a T-maze reversal procedure that was very similar to previous studies except that positive, appetitive reinforcement was used for motivation. The results showed that MIA animals performed similarly to controls during training, but in contrast to the previous, aversively motivated T-maze studies, slower reversal learning was observed. These results show that MIA animals are impaired in reversal learning under conditions of positive reinforcement, consistent with the effects observed in individuals with schizophrenia. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Maternal immune activation altered microglial immunoreactivity in the brain of postnatal day 2 rat offspring.

Microglia, the resident immune cells of the central nervous system, play critical roles in neurodevelopment, synaptic pruning, and neuronal wiring. Early in development, microglia migrate via the tangential and radial migration pathways to their final destinations and mature gradually, a process that includes morphological changes. Recent research has implicated microglial abnormality in the etiology of schizophrenia. Since prenatal exposure to viral or bacterial infections due to maternal immune activation (MIA) leads to increased risk of schizophrenia in the offspring during adulthood, the present study systematically investigated how MIA induced by polyinosinic:polycytidylic acid (a mimic of viral double-stranded RNA) affected microglial immunoreactivity along the migration and maturation trajectories in the brains of male and female rat offspring on postnatal day (PND) 2. The immunohistochemistry revealed significant changes in the density of IBA-1 immunoreactive cells in the corpus callosum, somatosensory cortex, striatum, and the subregions of the hippocampus of the MIA offspring. The male and female MIA offspring displayed markedly altered microglial immunoreactivity in both the tangential and radial migration, as well as maturation, pathways when compared to their sex- and age-matched controls as evidenced by morphology-based cell counting. Given the important roles of microglia in synaptic pruning and neuronal wiring and survival, these changes may lead to structural and functional neurodevelopmental abnormalities, and so contribute to the functional deficits observed in juvenile and adult MIA offspring. Future research is required to systematically determine how MIA affects microglial migration and maturation in rat offspring.

Conflict and adaptation signals in the anterior cingulate cortex and ventral tegmental area.

The integration and utilization of feedback in order to determine which decision strategy to use in different contexts is the core of executive function. The anterior cingulate cortex (ACC) is central to these processes but how feedback is made available to the ACC is unclear. To address this question, we trained rats with implants in the ACC and the ventral tegmental area (VTA), a dopaminergic brain region implicated in feedback processing, in a spatial decision reversal task with rule switching occurring approximately every 12 trials. Following a rule switch, the rats had to shift and sustain responses to the alternative side in order to obtain reward. Partial directed coherence (PDC) models of signal directionality between the ACC and VTA indicated that VTA → ACC communication (near 4 Hz) increased immediately prior to incorrect choices and during post-error decisions. This increase did not occur during correct choices. These data indicate that the VTA provides a feedback-driven, bottom-up modulating signal to the ACC which may be involved in assessing, and correcting for, decision conflict.

Hippocampal place cell encoding of sloping terrain.

Effective navigation relies on knowledge of one's environment. A challenge to effective navigation is accounting for the time and energy costs of routes. Irregular terrain in ecological environments poses a difficult navigational problem as organisms ought to avoid effortful slopes to minimize travel costs. Route planning and navigation have previously been shown to involve hippocampal place cells and their ability to encode and store information about an organism's environment. However, little is known about how place cells may encode the slope of space and associated energy costs as experiments are traditionally carried out in flat, horizontal environments. We set out to investigate how dorsal-CA1 place cells in rats encode systematic changes to the slope of an environment by tilting a shuttle box from flat to 15 ° and 25 ° while minimizing external cue change. Overall, place cell encoding of tilted space was as robust as their encoding of flat ground as measured by traditional place cell metrics such as firing rates, spatial information, coherence, and field size. A large majority of place cells did, however, respond to slope by undergoing partial, complex remapping when the environment was shifted from one tilt angle to another. The propensity for place cells to remap did not, however, depend on the vertical distance the field shifted. Changes in slope also altered the temporal coding of information as measured by the rate of theta phase precession of place cell spikes, which decreased with increasing tilt angles. Together these observations indicate that place cells are sensitive to relatively small changes in terrain slope and that terrain slope may be an important source of information for organizing place cell ensembles. The terrain slope information encoded by place cells could be utilized by efferent regions to determine energetically advantageous routes to goal locations.

Spared motivational modulation of cognitive effort in a maternal immune activation model of schizophrenia risk.

Maternal immune activation (MIA) during gestation is a significant risk factor for development of schizophrenia and other neurodevelopmental diseases. In animal models of this risk factor, MIA during pregnancy can produce offspring that recapitulate certain aspects of the behavioral and neurophysiological impairments seen in schizophrenia. Here, the authors tested the effect of polyinosinic-polycytidylic acid (poly I:C)-induced MIA in a task that explicitly assays the interaction between motivation and cognition. In our paradigm, discrimination accuracy during a sustained-attention task is differentially impacted by environmental cues that signal the probability of reward for accurate performance. Cognition-motivation interactions are implicated in producing functional impairments in patients. Therefore, to the extent that this MIA model recapitulates such impairments, the authors predicted impaired ability of reward-associated signals to modulate cognitive performance in MIA rat offpsring. Adult offspring of dams in which MIA was induced displayed impaired prepulse inhibition relative to controls, verifying a functional effect of poly I:C induction. Despite this deficit, there were no differences between MIA and control rats in any aspects of task learning or performance, including under extinction and reacquisition conditions. These results indicate that MIA spares functioning of some of the cognitive, motivational, and decision-making processes that are impacted in schizophrenia and suggest that MIA as an isolated manipulation does not model the full range and nuance of the cognitive and motivational impairments in the disease. The authors suggest that some aspects of the functional impairment in schizophrenia and other neurodevelopmental diseases may be better modeled using multiple "hit" models of disease risk. (PsycINFO Database Record