Affective States and Large-scale Network Activity

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

Abstract Proper hedonic processing is vital to perform motivated behaviors, but it can be disrupted by different psychiatric illnesses (e.g., substance use disorder and depression). Such disruption can lead to the development of negative affective states prevalent in suicide victims and during the craving/withdrawal phase of SUDs, contributing to relapse. While neural mechanisms mediating negative affect in depression and SUDs overlap, the neural changes produced by one makes the brain more susceptible to the other illness, increasing the risk of comorbidity. Considering that neuropsychiatric disorders are associated with dysfunction within large-scale brain networks, the overall goal of this project is to understand the global impact of different kinds of learned negative affect in such network activity. To do so, I will use taste reactivity (TR) to measure affective states in rats, in which aversive and appetitive orofacial responses to an intraorally infused solution are analyzed. To study the development of learned negative affect, I will combine TR with conditioned taste aversion (CTA), in which pairing a sweet tastant (e.g., saccharin) with a malaise-producing agent such as Lithium Chloride (LiCl), can shift the affective response of the rat from appetitive to aversive. Interestingly, while LiCl CTA is developed exclusively due to the aversive properties of the drug, such conditioned aversion can also be developed to agents that are not a priori aversive, such as drugs of abuse (e.g., cocaine). Importantly, while LiCl CTA allows us to model negative affect associated to unequivocal aversive experiences, drug CTA allow us to model complex aspects of addiction, such as natural reward devaluation and cue-induced withdrawal. Additionally, it has been shown that affect in general, and negative affect in particular, are differentially encoded across sex. To study the underlying differences between LiCl and cocaine CTA in male and female rats, I propose 2 Aims in the mentored phase and 2 aims in the independent phase of this application. Aim 1 (K99 phase) of this proposal will use rodent functional magnetic resonance (fMRI) and TR to investigate the effects of LiCl CTA on resting state (RS) activity in large-scale brain networks, including the default mode network (DMN), the lateral cortical network (LCN) and the salience network (SN) in male and female rats. Aim 2 (K99 phase) will use a highly novel multi-spectral, four-channel fiber photometry method and TR to examine how key nodes within the DMN and SN respond to the taste infusion after LiCl CTA development in male and female rats. Aim 3 (R00 phase) will use fMRI and TR to study the impact of cocaine CTA on brain network RS activity. Aim 4 (R00 phase) will use TR and fiber photometry in key nodes of the DMN and the SN to examine their response to the taste cue after cocaine CTA development. Collectively, these studies will provide critical insight into how brain networks and key nodes within them are altered after the development of two distinct forms of negative affect (LiCl and cocaine CTA).