Document text
Principal Investigator: William A. Carlezon
Organization: MCLEAN HOSPITAL
Fiscal Year: 2024
Award: $569,913
Funding agency: National Institute of Mental Health
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.
Terms: <Ablation><Address><Affect><Affective Disorders><Animal Model><Animal Models and Related Studies><Anti-Anxiety Agents><Anti-Anxiety Drugs><Anxiety Disorders><Anxiolytic Agents><Anxiolytics><Basal Transcription Factor><Basal transcription factor genes><Behavior><Behavioral><Biological><Body Temperature><Brain><Brain Nervous System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 affected><COVID-19 consequence><COVID-19 crisis><COVID-19 effect><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CREB><CREB1><CREB1 gene><Causality><Cell Body><Cells><Cellular Immune Function><Characteristics><Chronic stress><Clinical Trials><Cognition><Cognitive><Common Rat Strains><Complex><Data><Development><Diagnosis><Diurnal Rhythm><Dynorphins><EEG><Electroencephalogram><Electroencephalography><Emotional Depression><Encephalon><Equilibrium><Etiology><Event-Related Potentials><Female><Foundations><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Glia><Glial Cells><Goals><Grant><Hortega cell><Human><Immune><Immune Cell Activation><Immune response><Immune system><Immunes><Immunological response><Inflammation><Intervention><Intervention Strategies><Kolliker's reticulum><Life><Ligands><Measurement><Mediating><Mental Depression><Mental disorders><Mental health disorders><Mice><Mice Mammals><Microglia><Minor Tranquilizing Agents><Modeling><Modern Man><Molecular><Mood Disorders><Motivation><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurons><Non-neuronal cell><Nonneuronal cell><Nucleus Accumbens><Opiate Antagonist><Opiate receptor antagonist><Opioid Antagonist><Opioid receptor antagonist><Performance><Phenotype><Play><Population><Predictive Value><Predisposition><Procedures><Process><Psychiatric Disease><Psychiatric Disorder><Psychiatry><Psychopathology><RNA Expression><Rat><Rats Mammals><Rattus><Receptor Signaling><Regimen><Regulation><Research><Rodent><Rodentia><Rodents Mammals><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Single-Nucleus Sequencing><Sleep><Sleep Architecture><Sleep disturbances><Stress><Susceptibility><Symptoms><System><Task Performances><Testing><Therapeutic Effect><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Up-Regulation><Upregulation><Work><aberrant sleep><abnormal psychology><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><balance><balance function><biologic><cAMP Response Element-Binding Protein 1><causation><cell type><cognitive control><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 effect><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 impact><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 impact><coronavirus disease-19 pandemic><depression><depression symptom><depressive><depressive behavior><depressive symptoms><developmental><disease causation><disrupted sleep><disturbed sleep><diurnal variation><early life stress><event related potential><experience><gitter cell><host response><human tissue><immune activation><immune function><immune system response><immunoresponse><impaired sleep><improved><in vivo><innovate><innovation><innovative><insight><interventional strategy><irregular sleep><kappa opiate><kappa opioid><kappa opioid receptors><life span><lifespan><male><mental illness><mesoglia><microglial cell><microgliocyte><model of animal><nerve cement><neuronal><novel><perivascular glial cell><programs><psychiatric illness><psychological disorder><receptor expression><receptor function><resilience><resilience factor><resiliency factor><resilient><resilient to stress><response><sNuc-Seq><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><sleep control><sleep disruption><sleep dysregulation><sleep regulation><snRNA sequencing><snRNA-seq><social role><stress resilience><stress resiliency><stressor><tool><transcription factor><virtual><κ opiate><κ opioid><κ opioid receptors><κ-OR><κOR>