Multiunit cluster firing patterns of piriform cortex and mediodorsal thalamus in absence epilepsy.

OBJECTIVE: The objective of the study were to investigate patterns of multiunit cluster firing in the piriform cortex (PC) and mediodorsal thalamus (MDT) in a rat model of genetic generalized epilepsy (GGE) with absence seizures and to assess whether these regions contribute to the initiation or spread of generalized epileptiform discharges. METHODS: Multiunit clusters and their corresponding local field potentials (LFPs) were recorded from microelectrode arrays implanted in the PC and MDT in urethane anesthetized Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and nonepileptic control (NEC) rats. Peristimulus time histograms (PSTHs) and cross-correlograms were used to observe transient changes in both the rate of firing and synchrony over time. The phase locking of multiunit clusters to LFP signals (spike-LFP phase locking) was calculated for frequency bands associated with olfactory communication between the two brain regions. RESULTS: There were significant increases in both rate of firing and synchronous activity at the onset of generalized epileptiform discharges in both PC and MDT. Prior to and following these increases in synchronous activity, there were periods of suppression. Significant increases in spike-LFP phase locking were observed within the PC prior to the onset of epileptiform discharges across all spectral bands. There were also significant increases in spike-LFP phase locking within the theta band of the MDT prior to onset. Between the two brain regions, there was a significant decrease in spike-LFP phase locking -0.5 s prior to onset in the theta band which coincided with a significant elevation in spike-LFP phase locking in the gamma band. CONCLUSIONS: Both the PC and MDT are engaged in the absence epilepsy network. Early spike-LFP phase locking between these two brain regions suggests potential involvement in the initiation of seizure activity.

Disconnection of basolateral amygdala and insular cortex disrupts conditioned approach in Pavlovian lever autoshaping.

Previously established individual differences in appetitive approach and devaluation sensitivity observed in goal- and sign-trackers may be attributed to differences in the acquisition, modification, or use of associative information in basolateral amygdala (BLA) pathways. Here, we sought to determine the extent to which communication of associative information between BLA and anterior portions of insular cortex (IC) supports ongoing Pavlovian conditioned approach behaviors in sign- and goal-tracking rats, in the absence of manipulations to outcome value. We hypothesized that the BLA mediates goal-, but not sign- tracking approach through interactions with the IC, a brain region involved in supporting flexible behavior. We first trained rats in Pavlovian lever autoshaping to determine their sign- or goal-tracking tendency. During alternating test sessions, we gave unilateral intracranial injections of vehicle or a cocktail of gamma-aminobutyric acid (GABA) receptor agonists, baclofen and muscimol, unilaterally into the BLA and contralaterally or ipsilaterally into the IC prior to reinforced lever autoshaping sessions. Consistent with our hypothesis we found that contralateral inactivation of BLA and IC increased the latency to approach the food cup and decreased the number of food cup contacts in goal-trackers. While contralateral inactivation of BLA and IC did not affect the total number of lever contacts in sign-trackers, this manipulation increased the latency to approach the lever. Ipsilateral inactivation of BLA and IC did not impact approach behaviors in Pavlovian lever autoshaping. These findings, contrary to our hypothesis, suggest that communication between BLA and IC maintains a representation of initially learned appetitive associations that commonly support the initiation of Pavlovian conditioned approach behavior regardless of whether it is directed at the cue or the location of reward delivery.

Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 µg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

Anatomical imaging of the piriform cortex in epilepsy.

The piriform cortex is a distinct brain region that plays a key role in the sense of smell. The piriform cortex is the major part of primary olfactory cortex and has broad connections that extend beyond the olfactory regions into limbic and fronto-temporal cortical networks. Numerous studies have described these anatomical connections via microscopic imaging and tracer studies. More recently, macroscopic anatomical imaging studies have demonstrated changes in the piriform cortex in humans with focal epilepsy as well as in animal models, suggesting this brain region can play a critical role in epileptogenesis. This review examines the imaging methods and techniques that have been most informative, leading to our current understanding of the anatomy and subdivsions of the piriform cortex as well as its connections to other brain structures, and the abnormalities that can be detected in the setting of epilepsy.

Cannabinoid receptor-1 signaling contributions to sign-tracking and conditioned reinforcement in rats.

RATIONALE: Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking. OBJECTIVES: Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test. METHODS: In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test. RESULTS: Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker's latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement. CONCLUSIONS: Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior.

The Dopamine Prediction Error: Contributions to Associative Models of Reward Learning.

Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto's (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. This is argued to endow the reward-predictive cue with the value inherent in the reward, motivating behavior toward cues signaling the presence of reward. Yet theoretical and empirical research has implicated prediction-error signaling in learning that extends far beyond a transfer of quantitative value to a reward-predictive cue. Here, we review the research which demonstrates the complexity of how dopaminergic prediction errors facilitate learning. After briefly discussing the literature demonstrating that phasic dopaminergic signals can act in the manner described by Sutton and Barto (1981), we consider how these signals may also influence attentional processing across multiple attentional systems in distinct brain circuits. Then, we discuss how prediction errors encode and promote the development of context-specific associations between cues and rewards. Finally, we consider recent evidence that shows dopaminergic activity contains information about causal relationships between cues and rewards that reflect information garnered from rich associative models of the world that can be adapted in the absence of direct experience. In discussing this research we hope to support the expansion of how dopaminergic prediction errors are thought to contribute to the learning process beyond the traditional concept of transferring quantitative value.

Cue-induced food seeking after punishment is associated with increased Fos expression in the lateral hypothalamus and basolateral and medial amygdala.

In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking. We trained male rats to lever press for food pellets that were delivered after a 10-s conditional stimulus (CS) (appetitive). Following training, 25% of reinforced lever presses resulted in the presentation of a compound stimulus consisting of a novel CS (aversive) and the appetitive CS followed by a pellet and footshock. After punishment-imposed abstinence, we tested the rats in an extinction test where lever pressing resulted in the presentation of either the appetitive or aversive CS. We then compared activity of lateral hypothalamus (LH) and associated extrahypothalamic regions following this test. We also assessed Fos expression in LH orexin and GABA neurons. We found that cue-induced relapse of food seeking on test was higher in rats tested with the appetitive CS compared to the aversive CS. Relapse induced by the appetitive CS was associated with increased Fos expression in LH, caudal basolateral amygdala (BLA), and medial amygdala (MeA). This relapse was also associated with increased Fos expression in LH orexin and VGAT-expressing neurons. These data show that relapse to food seeking can be induced by food-associated cues after punishment-imposed abstinence, and this relapse is associated with increased activity in LH, caudal BLA, and MeA. (PsycINFO Database Record

Individual variability in behavioral flexibility predicts sign-tracking tendency.

Sign-tracking rats show heightened sensitivity to food- and drug-associated cues, which serve as strong incentives for driving reward seeking. We hypothesized that this enhanced incentive drive is accompanied by an inflexibility when incentive value changes. To examine this we tested rats in Pavlovian outcome devaluation or second-order conditioning prior to the assessment of sign-tracking tendency. To assess behavioral flexibility we trained rats to associate a light with a food outcome. After the food was devalued by pairing with illness, we measured conditioned responding (CR) to the light during an outcome devaluation probe test. The level of CR during outcome devaluation probe test correlated with the rats' subsequent tracking tendency, with sign-tracking rats failing to suppress CR to the light after outcome devaluation. To assess Pavlovian incentive learning, we trained rats on first-order (CS+, CS-) and second-order (SOCS+, SOCS-) discriminations. After second-order conditioning, we measured CR to the second-order cues during a probe test. Second-order conditioning was observed across all rats regardless of tracking tendency. The behavioral inflexibility of sign-trackers has potential relevance for understanding individual variation in vulnerability to drug addiction.

Appetitive-aversive interactions in Pavlovian fear conditioning.

The existence of value coding and salience coding neurons in the mammalian brain, including in habenula and ventral tegmental area, has sparked considerable interest in the interactions that occur between Pavlovian appetitive and aversive conditioning. Here we studied these appetitive-aversive interactions at the behavioral level by assessing the learning that occurs when a Pavlovian appetitive conditioned stimulus (conditional stimulus, CS) serves as a CS for shock in Pavlovian fear conditioning. A Pavlovian appetitive CS was retarded in the rate at which it could be transformed into a fear CS (counterconditioning), but the presence of the appetitive CS augmented fear learning to a concurrently presented neutral CS (superconditioning). Retardation of fear learning was not alleviated by manipulations designed to restore the associability of the appetitive CS before fear conditioning but was alleviated by manipulations designed to increase the aversive quality of the shock unconditioned stimulus (US). These findings are consistent with opponent interactions between the appetitive and aversive motivational systems and provide a behavioral approach for assessing the neural correlates of these appetitive-aversive interactions.