title: Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART).
abstract: Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is mediated in part through projections from hypothalamic peptide transmitter systems such as cocaine- and amphetamine-regulated transcript (CART). Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behavior in an animal model of contingent cocaine self-administration. Despite this work, few studies have assessed how the basic physiological properties of PVT neurons are influenced by exposure to drugs such as cocaine. Further, our previous work did not assess how infusions of CART, which we found to decrease cocaine-seeking, altered the activity of PVT neurons. In the current study we address these issues by recording from anterior PVT (aPVT) neurons in acutely prepared brain slices from cocaine-treated (15 mg/ml, n = 8) and saline-treated (control) animals (n = 8). The excitability of aPVT neurons was assessed by injecting a series of depolarizing and hyperpolarizing current steps and characterizing the resulting action potential (AP) discharge properties. This analysis indicated that the majority of aPVT neurons exhibit tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF) patterns. Interestingly, cocaine exposure significantly increased the proportion of aPVT neurons that exhibited TF. We then investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. Application of CART significantly suppressed excitatory synaptic drive to PVT neurons in both cocaine-treated and control recordings. This finding is consistent with our previous behavioral data, which showed that CART signaling in the PVT negatively regulates drug-seeking behavior. Together, these studies suggest that cocaine exposure shifts aPVT neurons to a more excitable state (TF). We propose that the capacity of CART to reduce excitatory drive to this population balances the enhanced aPVT excitability to restore the net output of this region in the reward-seeking pathway. This is in line with previous anatomical evidence that the PVT can integrate reward-relevant information and provides a putative mechanism through which drugs of abuse can dysregulate this system in addiction.
authors.affiliation: Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, and The Centre for Translational Neuroscience and Mental Health Research, University of Newcastle and the Hunter Medical Research Institute Newcastle, NSW, Australia.
authors.forename: Jiann Wei
authors.initials: JW
authors.lastname: Yeoh
authors.affiliation: Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, and The Centre for Translational Neuroscience and Mental Health Research, University of Newcastle and the Hunter Medical Research Institute Newcastle, NSW, Australia.
authors.forename: Morgan H
authors.initials: MH
authors.lastname: James
authors.affiliation: Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, and The Centre for Translational Neuroscience and Mental Health Research, University of Newcastle and the Hunter Medical Research Institute Newcastle, NSW, Australia.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Graham
authors.affiliation: Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, and The Centre for Translational Neuroscience and Mental Health Research, University of Newcastle and the Hunter Medical Research Institute Newcastle, NSW, Australia.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Dayas
keywords: CART; PVT; addiction; cocaine; electrophysiology; midline thalamus; reward-seeking