Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease (≈50%) of reelin expression. In this study we measured Purkinje neuron density in the Purkinje cell layer of cerebella of 13 SZ and 17 BP disorder patients from the McLean 66 Cohort Collection, Harvard Brain Tissue Resource Center. The mean number of Purkinje neurons (linear density, neurons per millimeter) was 20% lower in SZ and BP disorder patients compared with nonpsychiatric subjects (NPS; n = 24). This decrease of Purkinje neuron linear density was unrelated to postmortem interval, pH, drugs of abuse, or to the presence, dose, or duration of antipsychotic medications. A comparative study in the cerebella of heterozygous reeler mice (HRM), in which reelin expression is downregulated by ≈50%, showed a significant loss in the number of Purkinje cells in HRM (10-15%) compared with age-matched (3-9 months) wild-type mice. This finding suggests that lack of reelin impairs GABAergic Purkinje neuron expression and/or positioning during cerebellar development.A number of behavioral, neuropathologic, neuroimaging, and neurochemical studies suggest that the cerebellum may be defective in schizophrenia (SZ) (for a review see ref. 1). We (2, 3) and others (4) have reported that cerebella from SZ and bipolar (BP) disorder patients exhibit a 50% decrease in the expression of glutamic acid decarboxylase 67 (GAD67), which is a major GABA synthesizing enzyme present in cerebellar Purkinje neurons. This decrease suggests that these GABAergic principal neurons may be damaged. We also reported that in the cerebellar glutamatergic granule cells of SZ and BP disorder patients, there is a marked decrease of reelin mRNA levels (2, 3).A decrease of reelin levels in the cerebellum of SZ patients has been confirmed in other studies (4). In addition, the reduction of reelin mRNA is negatively correlated with the expression of the transcription factor semaphorin 3A in the cerebella of subjects with SZ (5).Reelin is a large (≈400 kDa) extracellular matrix protein synthesized by GABAergic interneurons in the telencephalon and by glutamatergic granule cells in the cerebellum (6-9). It is secreted extracellularly by constitutive mechanisms (10) and is believed to play a significant role in glutamate receptor homeostasis and spine formation in the adult brain (11)(12)(13)(14).The heterozygous reeler mouse (HRM), which expresses ≈50% of the amount of reelin present in brains of wild-type mice (WTM), displays certain behavioral and anatomic abnormalities reminiscent of those found in SZ patients. These include (i) prepulse inhibition deficits, which are a measure of sensory motor gating of the CNS (15), (ii) contextual fear conditioning deficits, which are a measure of a hippocampal/amygdaladependent function (16), and (iii) long-te...

Cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the sign-tracker/goal-tracker animal model. Goal-trackers attribute predictive value to reward-cues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goal-trackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction.

Rationale The paraventricular nucleus of the thalamus (PVT) has been shown to mediate cue-motivated behaviors, such as sign- and goal-tracking, as well as reinstatement of drug-seeking behavior. However, the role of the PVT in mediating individual variation in cue-induced drug-seeking behavior remains unknown. Objectives To determine if inactivation of the PVT differentially mediates cue-induced drug-seeking behavior in sign-trackers and goal-trackers. Methods Rats were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their Pavlovian conditioned approach behavior. Rats were then exposed to 15 days of cocaine self-administration, followed by a 2-week forced abstinence period and then extinction training. Rats then underwent tests for cue-induced reinstatement and general locomotor activity, prior to which they received an infusion of either saline (control) or baclofen/muscimol (B/M) to inactivate the PVT. Results Relative to control animals of the same phenotype, GTs show a robust increase in cue-induced drug-seeking behavior following PVT inactivation, whereas the behavior of STs was not affected. PVT inactivation did not affect locomotor activity in either phenotype. Conclusion In GTs, the PVT appears to inhibit the expression of drug seeking, presumably by attenuating the incentive value of the drug cue. Thus, inactivation of the PVT releases this inhibition in GTs, resulting in an increase in cue-induced drug-seeking behavior. PVT inactivation did not affect cue-induced drug-seeking behavior in STs, suggesting that the role of the PVT in encoding the incentive motivational value of drug cues differs between STs and GTs.

Stimuli or cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the signtracker/goal-tracker animal model. Goal-trackers attribute predictive value to rewardcues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goaltrackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction. independent delivery of food-US, distinct conditioned responses emerge. Some rats, goal-trackers (GTs), approach the location of impending food delivery upon the lever-CS presentation, while others, sign-trackers (STs), approach and interact with the lever-CS itself. For both GTs and STs the lever-CS acquires predictive value and elicits a conditioned response, but for STs, the CS also acquires incentive value. This animal model, therefore, provides a unique platform to investigate the neurobiological determinants of individual differences in the propensity to attribute incentive salience to reward-cues.Previous studies suggest that sign-tracking behavior results from enhanced activity in subcortical brain circuits known to mediate motivated behaviors, including the striatal dopamine system, the amygdala, and the hypothalamus 22,23,28-31 . In addition, relative to GTs, STs appear to have deficits in top-down cognitive control originating in the prefrontal cortex 32 . Thus, we hypothesize that sign-tracking behavior arises from an imbalance between top-down cognitive control and bottom-up motivational processes.One brain region that is ideally situated to act as a fulcrum between cortical, limbic and homeostatic circuits is the paraventricular nucleus of the thalamus (PVT). The PVT has, in fact, come to be known as the "thalamic gateway" 33 for appetitive motivation; acting to integrate cognitive, emotional, motivational and viscerosensitive information, and, in turn, guide behavioral responses 33,34 . Consistent with this view, the PVT has been implicated in the propensity to attribute incentive motivational value to reward-cues [35][36][37] .The functional connectivity of the PVT in response to cue-induced neuronal activity differentiates STs from GTs 28,29,35 . In STs, cue-induced activity in the PVT is correlated with activity in subcortical areas, including the nucleus accumbens (NAc); whereas in GTs, cue-...

Injections of the GABAA antagonist bicuculline into the medial ventral pallidum (VPm) induce marked increases in food intake, but nothing is known about the way in which these injections alter the distribution of intake in a macronutrient selection situation. We investigated this topic by adapting rats to a diet containing independent sources of protein, carbohydrate and fat, and then examining the effects of intra-VPm bicuculline on diet selection. Under these conditions, bicuculline produced a massive, preferential increase in fat intake with subjects consuming a mean of 97% of their calories from fat. Furthermore, all treated subjects ate fat before any other macronutrient, suggesting that the animals' behavior was directed selectively toward this dietary component even before consumption had begun. Similar effects were not observed following food deprivation, which exerted its largest effect on carbohydrate intake. To compare the intra-VPm bicuculline response to that seen after activation of GABA receptors in the nucleus accumbens shell (AcbSh), a major source of projections to the VPm, we conducted similar experiments with intra-AcbSh injections of muscimol and baclofen. These injections also enhanced food intake, but did not reproduce the selective preference for fat seen after intra-VPm bicuculline. These experiments provide the first demonstration of preferential enhancement of fat intake following manipulations of a nonpeptide neurotransmitter. Since mean intakes of fat under baseline conditions and after deprivation tended to be lower than those of carbohydrates, it seems unlikely that the effects of intra-VPm bicuculline are related to the intrinsic "rewarding" properties of fat, but might rather reflect the induction of a state of "fat craving."