Histone deacetylase 5 in prelimbic prefrontal cortex limits context-associated cocaine seeking.

Background: Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear.

Methods: In the rat intravenous cocaine self-administration (SA) model, we examined the role and regulation of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking.

The activity-regulated cytoskeleton-associated protein (Arc) functions in a cell type- and sex-specific manner in the adult nucleus accumbens to regulate non-contingent cocaine behaviors.

Repeated cocaine use produces adaptations in brain function that contribute to long-lasting behaviors associated with cocaine use disorder (CUD). In rodents, the activity-regulated cytoskeleton-associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)-a brain region linked to CUD-related behavior. We show here that repeated, non-contingent cocaine administration in global Arc KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience-dependent sensitization of conditioned place preference (CPP).

NPAS4 supports cocaine-conditioned cues in rodents by controlling the cell type-specific activation balance in the nucleus accumbens.

Powerful associations that link drugs of abuse with cues in the drug-paired environment often serve as prepotent relapse triggers. Drug-associated contexts and cues activate ensembles of nucleus accumbens (NAc) neurons, including D1-class medium spiny neurons (MSNs) that typically promote, and D2-class MSNs that typically oppose, drug seeking. We found that in mice, cocaine conditioning upregulated transiently the activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), in a small subset of NAc neurons.

Differential Roles of Oxytocin Receptors in the Prefrontal Cortex and Nucleus Accumbens on Cocaine Self-Administration and Reinstatement of Cued Cocaine Seeking in Male Rats.

Background: Little is known about the specific roles of cortical and accumbal oxytocin receptors in drug use disorders. To better understand the importance of the endogenous oxytocin system in cocaine relapse behavior, we developed an adeno-associated viral vector-expressing short hairpin (sh) RNAs to selectively degrade the rat oxytocin receptor (OxyR) mRNA in vivo.

Methods: Male (Sprague-Dawley) rats received bilateral infusions of the shRNA for the oxytocin receptor (shOxyR) or an shRNA control virus into the prefrontal cortex (PFC) or the nucleus accumbens core (NAc).

The activity-regulated cytoskeleton-associated protein, Arc, functions in the nucleus accumbens shell to limit multiple triggers of cocaine-seeking behaviour.

Use of addictive substances like cocaine produces enduring associations between the drug experience and cues in the drug-taking environment. In individuals with a substance use disorder (SUD) and attempting to remain abstinent, these powerful drug-cue associations can trigger a return to active drug use, but the molecular mechanisms regulating drug-cue associations remain poorly understood. The activity-regulated cytoskeleton-associated protein (Arc) is induced by cocaine in the nucleus accumbens (NAc), an important brain reward region, but Arc's NAc function in SUD-related behaviour remains unclear.

The activity-regulated cytoskeleton-associated protein, Arc/Arg3.1, influences mouse cocaine self-administration.

The activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1), an immediate early gene and synaptic regulator, is upregulated following a single cocaine exposure. However, there is not much known regarding Arc/Arg3.

Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) regulates anxiety- and novelty-related behaviors.

The activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc)-a brain region implicated in mood and anxiety behaviors.

Methamphetamine Self-Administration Elicits Sex-Related Changes in Postsynaptic Glutamate Transmission in the Prefrontal Cortex.

Preclinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge, we recorded from the prelimbic area of the prefrontal cortex (PL-PFC) of male and female rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during SA; however, female rats exhibit significant synaptic baseline differences when compared to males.

It is a complex issue: emerging connections between epigenetic regulators in drug addiction.

Drug use leads to addiction in some individuals, but the underlying brain mechanisms that control the transition from casual drug use to an intractable substance use disorder (SUD) are not well understood. Gene x environment interactions such as the frequency of drug use and the type of substance used likely to promote maladaptive plastic changes in brain regions that are critical for controlling addiction-related behavior. Epigenetics encompasses a broad spectrum of mechanisms important for regulating gene transcription that are not dependent on changes in DNA base pair sequences.

Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons.

HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors.

Individuals suffering from substance-use disorders develop strong associations between the drug's rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression.

Novel role and regulation of HDAC4 in cocaine-related behaviors.

Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)-key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm-a process controlled in large part by changes in phosphorylation of conserved residues.

Assessment of Cocaine-induced Behavioral Sensitization and Conditioned Place Preference in Mice.

It is thought that rewarding experiences with drugs create strong contextual associations and encourage repeated intake. In turn, repeated exposures to drugs of abuse make lasting alterations in the brain function of vulnerable individuals, and these persistent alterations likely serve to maintain the maladaptive drug seeking and taking behaviors characteristic of addiction/dependence(2). In rodents, reward experience and contextual associations are frequently measured using the conditioned place preference assay, or CPP, wherein preference for a previously drug-paired context is measured.

Use of Adeno-Associated and Herpes Simplex Viral Vectors for In Vivo Neuronal Expression in Mice.

Adeno-associated viruses and the herpes simplex virus are the two most widely used vectors for the in vivo expression of exogenous genes. Advances in the development of these vectors have enabled remarkable temporal and spatial control of gene expression. This unit provides methods for storing, delivering, and verifying expression of adeno-associated and herpes simplex viruses in the adult mouse brain.

The presence of cortical neurons in striatal-cortical co-cultures alters the effects of dopamine and BDNF on medium spiny neuron dendritic development.

Medium spiny neurons (MSNs) are the major striatal neuron and receive synaptic input from both glutamatergic and dopaminergic afferents. These synapses are made on MSN dendritic spines, which undergo density and morphology changes in association with numerous disease and experience-dependent states. Despite wide interest in the structure and function of mature MSNs, relatively little is known about MSN development.

Nicotine trained as a negative feature passes the retardation-of-acquisition and summation tests of a conditioned inhibitor.

Nicotine functions as a negative feature in a Pavlovian discriminated goal-tracking task. Whether withholding of responding to the conditional stimulus (CS) reflects nicotine functioning as a conditioned inhibitor is unknown. Accordingly, the present research sought to determine whether nicotine trained as a negative feature passed the retardation-of-acquisition and summation tests, thus characterizing it as a pharmacological (interoceptive) conditioned inhibitor.

An embryonic culture system for the investigation of striatal medium spiny neuron dendritic spine development and plasticity.

Dendritic spines of striatal Medium Spiny Neurons (MSNs) receive converging dopaminergic and glutamatergic inputs. These spines undergo experience-dependent structural plasticity following repeated drug administration and during disease states like Huntington's and Parkinson's. Thus, understanding the molecular mechanisms leading to structural plasticity is an important step toward establishing a clear relationship between spine structure and function, and will ultimately contribute to understanding how changes in dendritic spine structure relate to behaviors or diseases.

Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration.

The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring.

Nicotine-evoked conditioned responding is dependent on concentration of sucrose unconditioned stimulus.

Previous studies have shown that the interoceptive nicotine conditional stimulus (CS) functions similarly to exteroceptive CSs such as lights or environments. For instance, the appetitive conditioned response (CR) evoked when nicotine is repeatedly paired with sucrose presentations (the unconditioned stimulus; US) is sensitive to changes in training dose (CS salience) and the contiguity between the CS effects and sucrose. The current study was conducted to extend this research by examining the possible role of US intensity in CR acquisition and maintenance.

Nicotine does not produce state-dependent effects on learning in a Pavlovian appetitive goal tracking task with rats.

Past research has shown that when rats received 0.4mg base/kg nicotine paired reliably with intermittent sucrose delivery that anticipatory sucrose-seeking behavior (i.e.

Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as a function of the number of conditioning trials and unpaired sucrose deliveries.

In rats, the pharmacological (interoceptive) effects of nicotine can serve as a signal (conditional stimulus) in a Pavlovian (classical) conditioning task. In this task, nicotine administration (0.4 mg base/kg, subcutaneous) is typically paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions.

Social cognitive bias and neurocognitive deficit in paranoid symptoms: evidence for an interaction effect and changes during treatment.

Persistent paranoid symptoms are best understood as having multiple causal mechanisms. An enhanced multidimensional understanding of paranoia may result from the convergence of two distinct measurement paradigms, experimental psychopathology and social cognitive research. This study investigated the role of neurocognitive deficits and emotion misperception bias as they relate to paranoid symptoms at two different time points in a sample of individuals with severe mental illness (primarily schizophrenia spectrum disorders [N=91]) undergoing intensive psychosocial rehabilitation.