Roles of nuleus accumbens CREB and Kappa function in depression

SUMMARY
This application is for competitive renewal of a grant that over its 20-year course has elucidated the ways in
which the function of the transcription factor CREB and kappa-opioid receptor (KOR) systems within the nucleus
accumbens (NAc) are changed by experience, including stress exposure, and how alterations in their function
affect behavior. We have shown that (a) stress upregulates NAc CREB and KOR signaling, (b) these effects
are sufficient to produce characteristic features of mood and anxiety disorders, and (c) disruption of CREB or
blockade of KORs produces antidepressant- and anxiolytic-like effects. Recently we have also shown a role for
these systems in sleep and biological (diurnal) rhythms, which are dysregulated across many types of psychiatric
illness. Our work has provided a basis for clinical trials of KOR antagonists to treat depression, which thus far
show great promise. Major goals for Years 21-25 are to further characterize the ways in which NAc CREB and
KOR systems regulate complex behavior and responses to different forms of stressors, including a type of
immune stress relevant to the COVID-19 pandemic, while prioritizing the use of endpoints in rodents with
improved alignment to those used in humans. In Aim 1, we will examine the mechanisms of CREB-mediated
depressive behavior using a new version of a cognitive control task (called the Flanker task) that we developed
to enable testing rats and humans using virtually identical procedures. Specifically, we will determine how
alterations in NAc CREB function in D1- and/or D2-medium spiny neurons (MSNs) affect task performance and
event-related potentials (ERPs)—endpoints known to be aberrant in human depression—in male and female
rats. In Aim 2, we will determine if a regimen of early immune activation (EIA) that produces long-lasting
depressive-like effects in mice causes persistent alterations in NAc CREB and KOR systems. Specifically, we
will use single-nucleus RNA sequencing to comprehensively examine EIA-induced alterations in NAc cell
populations, including MSNs and microglia, and compare and contrast effects in males and females. While
upregulation of NAc CREB and KOR systems is commonly associated with depressive phenotypes, in Aims 3-4
we will examine possible roles in stress resilience. For Aim 3, we will examine how KORs expressed on
microglia, which regulate immune function, affect sensitivity to stress. Specifically, we will examine how ablation
of KORs from microglia affects the ability of chronic stress to disrupt sleep and diurnal rhythms of activity and
body temperature. Similarly, in Aim 4 we will characterize the effects of altering the function of the CREB target
DFosB in D1- or D2-MSNs on stress-induced disruption of sleep and diurnal rhythms, while in parallel examining
effects on CREB, DYN, and KOR expression in NAc MSNs and microglia. All of these studies involve endpoints
(behavioral, molecular) that can also be studied in humans or human tissues. This work will improve our
understanding of the mechanisms by which NAc CREB and KOR function affect domains that are frequently
dysregulated in mood and anxiety disorders, and may enable new ways to diagnose and treat these conditions.

Grant Number: 5R01MH063266-25
NIH Institute/Center: NIH
Principal Investigator: William Carlezon