The glucocorticoid receptor as a top-down neuromolecular mechanism of inhibitory control

Abstract Environmental stimuli, or cues, can elicit maladaptive behavior. This is particularly observed in those with psychiatric disorders like substance use disorder (SUD), where a cue that is associated with prior drug use (e.g. paraphernalia), can result in relapse regardless of the individual’s desire to remain abstinent. Such cue- motivated behaviors are a result of behavioral disinhibition, or a lack of inhibitory control. Deficits in inhibitory control are broadly referred to as “impulsivity”, a term further defined by 1) heightenedكresponsiveness to reward-associated cues (i.e., reward sensitivity) and 2) impulsive actions conducted without regard to risk or consequences (i.e., rash impulsivity). Studies in humans and rodents show that individuals with heighted reward sensitivity also exhibit increased rash impulsivity. Both facets of impulsivity contribute to maladaptive behaviors, yet the neural underpinnings of these processes remain elusive. An overarching goal of this proposal is to determine whether both facets of impulsivity share the same neural mechanism. Specifically, this research focuses on a "top-down" inhibitory control pathway: the prelimbic cortex (PrL) to the nucleus accumbens core (NAcC). Glutamatergic projections from the PrL to the NAcC have been shown to modulate reward-seeking behavior and regulate NAcC dopamine (DA) activity. DA signaling in the NAcC also underlies impulsive action (rash impulsivity) and the attribution of incentive motivational value, or salience, to a reward cue (reward sensitivity). However, the mechanism by which these interactions occur within this pathway is unclear. The proposed research will investigate the glucocorticoid receptor (GR) as a neuromolecular mechanism within the PrL-NAcC pathway that regulates reward sensitivity and rash impulsivity via its effects on NAcC DA signaling. While the GR is known as a primary regulator of stress responsivity, it also regulates NAcC DA and plays a role in reward-related behaviors, including reward sensitivity. In addition, GR has been implicated in psychiatric conditions characterized by behavioral disinhibition. To examine the role of GR in inhibitory control processes, transgenic rats with conditional GR knockdown alleles will be employed to selectively knock down GR in PrL-NAcC projection neurons. Aim 1 will assess the effects of this manipulation on reward sensitivity using a Pavlovian conditioned approach paradigm that captures variability in the attribution of incentive salience to a reward cue. Aim 2 will assess the effects of GR knockdown on rash impulsivity using a Go/No-Go paradigm to measure the inability to withhold behavior in response to a cue. For both Aims, fast-scan cyclic voltammetry (FSCV) will be used to measure DA signaling within the NAcC in response to the reward-associated cue (Aim 1) and the “Go-“ and “No-go” cues (Aim 2). This research has the potential to uncover a neuromolecular mechanism of inhibitory control and, in turn, lead to better treatments for psychiatric disorders characterized by dysfunctional impulsivity.