Circuit-specific catecholamine regulation of sensitivity to delayed punishment - Abstract A fundamental characteristic of substance use disorder (SUD) is ongoing drug seeking and misuse despite physical, financial, and legal consequences. Critically, aversive consequences following a substantial delay, such as withdrawal after substance use, are often underestimated. Despite the common occurrence of delayed punishment, cost/benefit decision-making research has focused almost entirely on punishment occurring immediately after a choice. To address this gap, we developed the Delayed Punishment Decision-making Task (DPDT), which reveals that rats, like humans, underestimate or “discount” the negative value of delayed punishment during decision-making. Preliminary data obtained using DPDT reveal that orbitofrontal cortex (OFC) inactivation increases sensitivity to delayed punishment, and OFC encodes information about punishment delay prior to choice. While these data suggest a role of OFC in the assessment of delayed punishment, the mechanism underlying this process remains unclear. OFC activity is sculpted by catecholaminergic projections from distinct midbrain nuclei, specifically dopaminergic projections from the ventral tegmental area (VTA) and noradrenergic projections from the locus coeruleus (LC). Our central hypothesis is that sensitivity to delayed punishment is modulated by dopamine and norepinephrine projections to OFC, with dopamine release from neurons arising from VTA affecting the discounting of delayed punishment, and noradrenergic neurons from LC regulating sensitivity to punishment regardless of delay. We will evaluate this using DREADDS for both circuit and cell-type specific manipulation of neural activity in LC or VTA neurons projecting to OFC during DPDT. In Aim 1, we will use infuse inhibitory or excitatory DREADDS into the VTA of TH-Cre rats, then directly stimulate these receptors in the OFC terminals prior to DPDT. This will enable selective modulation of dopamine release in OFC. For Aim 2, we will infuse excitatory or inhibitory DREADDS into LC, then stimulate these receptors in OFC prior to DPDT. For all manipulations in both Aims, we will perform control experiments to confirm that manipulations are affecting sensitivity to immediate or delayed punishment rather than pain tolerance, reward discrimination, or behavioral flexibility. Collectively, these studies will determine a potential mechanism for how the OFC regulates sensitivity to both delayed and immediate punishment. Moreover, these experiments will determine if direct manipulation of two understudied neuronal circuits has efficacy as a potential treatment to improve sensitivity to delayed consequences in SUD.
