The function of the ZFP189 transcription factor in the nucleus accumbens facilitates cocaine-specific transcriptional and behavioral adaptations.

Distinguishing the brain mechanisms affected by distinct addictive drugs may inform targeted therapies against specific substance use disorders (SUDs). Here, we explore the function of a drug-associated, transcriptionally repressive transcription factor (TF), ZFP189, whose expression in the nucleus accumbens (NAc) facilitates cocaine-induced molecular and behavioral adaptations. To uncover the necessity of ZFP189-mediated transcriptional control in driving cocaine-induced behaviors, we created synthetic ZFP189 TFs of distinct transcriptional function, including ZFP189, which activates the expression of target genes and exerts opposite transcriptional control to the endogenously repressive ZFP189.

Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling.

Circuit-Wide Gene Network Analysis Reveals Sex-Specific Roles for Phosphodiesterase 1b in Cocaine Addiction.

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration.

CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use.

Background: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice.

Teenage drinking and adult neuropsychiatric disorders: An epigenetic connection.

Targeted epigenetic remodeling in the rat amygdala reverses the effects of adolescent alcohol consumption on excessive drinking and anxiety-like behavior in adulthood.

Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens.

Repeated cocaine use induces coordinated changes in gene expression that drive plasticity in the nucleus accumbens (NAc), an important component of the brain's reward circuitry, and promote the development of maladaptive, addiction-like behaviors. Studies on the molecular basis of cocaine action identify transcription factors, a class of proteins that bind to specific DNA sequences and regulate transcription, as critical mediators of this cocaine-induced plasticity. Early methods to identify and study transcription factors involved in addiction pathophysiology primarily relied on quantifying the expression of candidate genes in bulk brain tissue after chronic cocaine treatment, as well as conventional overexpression and knockdown techniques.

Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility.

Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility.

Methods: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression.

In vivo locus-specific editing of the neuroepigenome.

Studies over the past several decades have identified numerous epigenetic mechanisms associated with pathological states in psychiatric and neurological disease. Until recently, studies investigating chromatin-regulatory proteins, using overexpression or knockdown approaches, did not establish causal roles for epigenetic modifications at specific genes because these techniques typically affect hundreds or thousands of genomic loci. In this Review, we describe recent efforts in using locus-specific neuroepigenome editing in vivo to, for the first time, define causal relationships between a single chromatin modification at a specific gene in a defined cell population and downstream measures at the molecular, cellular, circuit and behavioural levels.

Intravenously Administered, Retinoid Activating Nanoparticles Increase Lifespan and Reduce Neurodegeneration in the SOD1 Mouse Model of ALS.

Dysregulation of the retinoic acid (RA) signaling pathway is observed in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here, we investigated the therapeutic potential of retinoid activation via the RA receptor β (RARβ) in the SOD1 mouse model of ALS. Our approach utilized the RARβ agonist adapalene, which we previously found to be neuroprotective Adapalene, like most retinoids, is poorly water soluble, which has thus far prevented effective drug delivery .

A positive genetic correlation between hypoxia tolerance and heat tolerance supports a controversial theory of heat stress.

We used quantitative genetics to test a controversial theory of heat stress, in which animals overheat when the demand for oxygen exceeds the supply. This theory, referred to as oxygen- and capacity-limited thermal tolerance, predicts a positive genetic correlation between hypoxia tolerance and heat tolerance. We demonstrate the first genetic correlation of this kind in a model organism, Genotypes more likely to fly under hypoxic stress (12% O) were also more likely to fly under heat stress (39°C).

Lizards fail to plastically adjust nesting behavior or thermal tolerance as needed to buffer populations from climate warming.

Although observations suggest the potential for phenotypic plasticity to allow adaptive responses to climate change, few experiments have assessed that potential. Modeling suggests that Sceloporus tristichus lizards will need increased nest depth, shade cover, or embryonic thermal tolerance to avoid reproductive failure resulting from climate change. To test for such plasticity, we experimentally examined how maternal temperatures affect nesting behavior and embryonic thermal sensitivity.