PKMζ alters oxycodone-taking in a dose- and sex-dependent manner.

Opioid use disorder involves disruptions to glutamate homeostasis and dendritic spine density in the reward system. PKMζ is an atypical isoform of protein kinase C that is expressed exclusively in neurons and plays a role in postsynaptic glutamate signaling and dendritic spine maturation. As opioid use leads to alterations in glutamate transmission and dendritic spine density, we hypothesized that PKMζ deletion would alter opioid-taking behaviors.

Sex differences in glutamate transmission and plasticity in reward related regions.

Disruptions in glutamate homeostasis within the mesolimbic reward circuitry may play a role in the pathophysiology of various reward related disorders such as major depressive disorders, anxiety, and substance use disorders. Clear sex differences have emerged in the rates and symptom severity of these disorders which may result from differing underlying mechanisms of glutamatergic signaling. Indeed, preclinical models have begun to uncover baseline sex differences throughout the brain in glutamate transmission and synaptic plasticity.

Post-weaning social isolation alters sociability in a sex-specific manner.

Adolescence is a critical period for brain development in humans and stress exposure during this time can have lasting effects on behavior and brain development. Social isolation and loneliness are particularly salient stressors that lead to detrimental mental health outcomes particularly in females, although most of the preclinical work on social isolation has been done in male animals. Our lab has developed a model of post-weaning adolescent social isolation that leads to increased drug reward sensitivity and altered neuronal structure in limbic brain regions.

Connecting self-report and instrumental behavior during incubation of food craving in humans.

Incubation of craving is a phenomenon describing the intensification of craving for a reward over extended periods of abstinence from reinforcement. Animal models use instrumental markers of craving to reward cues to examine incubation, while human paradigms rely on subjective self-reports. Here, we characterize an animal-inspired, novel human paradigm that showed strong positive relationships between self-reports and instrumental markers of craving for favored palatable foods.

Post-weaning social isolation alters sociability in a sex-specific manner.

Adolescence is a critical period for brain development in humans and stress exposure during this time can have lasting effects on behavior and brain development. Social isolation and loneliness are particularly salient stressors that lead to detrimental mental health outcomes particularly in females, although most of the preclinical work on social isolation has been done in male animals. Our lab has developed a model of post-weaning adolescent social isolation that leads to increased drug reward sensitivity and altered neuronal structure in limbic brain regions.

Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia.

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects.

Sex differences in pre- and post-synaptic glutamate signaling in the nucleus accumbens core.

Background: Glutamate signaling within the nucleus accumbens underlies motivated behavior and is involved in psychiatric disease. Although behavioral sex differences in these processes are well-established, the neural mechanisms driving these differences are largely unexplored. In these studies, we examine potential sex differences in synaptic plasticity and excitatory transmission within the nucleus accumbens core.

Circulating ovarian hormones interact with protein interacting with C kinase (PICK1) within the medial prefrontal cortex to influence cocaine seeking in female mice.

Protein interacting with C kinase 1 (PICK1) is an AMPA receptor binding protein that works in conjunction with glutamate receptor interacting protein (GRIP) to balance the number of GluA2-containing AMPARs in the synapse. In male mice, disrupting PICK1 in the medial prefrontal cortex (mPFC) leads to a decrease in cue-induced cocaine seeking and disrupting GRIP in the mPFC has the opposing effect, consistent with other evidence that removal of GluA2-containing AMPARs potentiates reinstatement. However, PICK1 does not seem to play the same role in female mice, as knockdown of either PICK1 or GRIP in the mPFC leads to similar increases in cue-induced cocaine seeking.

Sex differences in the medial prefrontal cortical glutamate system.

Background: Dysregulation in the prefrontal cortex underlies a variety of psychiatric illnesses, including substance use disorder, depression, and anxiety. Despite the established sex differences in prevalence and presentation of these illnesses, the neural mechanisms driving these differences are largely unexplored. Here, we investigate potential sex differences in glutamatergic transmission within the medial prefrontal cortex (mPFC).

Post-weaning social isolation causes sex-specific alterations to dendritic spine density in subregions of the prefrontal cortex and nucleus accumbens of adult mice.

Post-weaning social isolation stress has been shown to increase addiction-like behavior in adulthood. These long-term behavioral alterations may be due to long lasting isolation-induced structural changes to neurons in brain regions involved in reward processing. Previous studies have shown that various stressors alter dendritic spine density in the prefrontal cortex (PFC) and the nucleus accumbens, though many of these studies examine the short-term effects of stress, and are primarily conducted in males.

Adolescent social isolation induced alterations in nucleus accumbens glutamate signalling.

Exposure to adversity during early childhood and adolescence increases an individual's vulnerability to developing substance use disorder. Despite the knowledge of this vulnerability, the mechanisms underlying it are still poorly understood. Excitatory afferents to the nucleus accumbens (NAc) mediate responses to both stressful and rewarding stimuli.

Behavioral sex differences in cocaine and opioid use disorders: The role of gonadal hormones.

Females are more vulnerable than males to many aspects of cocaine use disorder. This vulnerability also translates to opioid use disorder, with females exhibiting stronger behavioral responses than males to drugs such as heroin and morphine. While there is evidence for many overlapping neural mechanisms underlying cocaine and opioid abuse, there is also a breadth of evidence indicating divergent effects of the drugs on synaptic plasticity.

Sex-specific role for prefrontal cortical protein interacting with C kinase 1 in cue-induced cocaine seeking.

Disruption of prefrontal glutamate receptor interacting protein (GRIP), which anchors GluA2-containing AMPA receptors (AMPARs) into the synaptic membrane, potentiates cue-induced cocaine seeking in both males and females. Protein interacting with C kinase 1 (PICK1) plays an opposing role to that of GRIP, removing AMPARs from the synapse. Consistent with our hypothesis that disruption of PICK1 in the mPFC would lead to a decrease in addiction-like behaviour, we found that conditional deletion of PICK1 in the mPFC attenuates cue-induced cocaine seeking in male mice.

Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes.

Experiencing some early life adversity can have an "inoculating" effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes.

Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation.

Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures.

A potential role for microglia in stress- and drug-induced plasticity in the nucleus accumbens: A mechanism for stress-induced vulnerability to substance use disorder.

Stress is an important risk factor for the development of substance use disorder (SUD). Exposure to both stress and drugs abuse lead to changes in synaptic plasticity and stress-induced alterations in synaptic plasticity may contribute to later vulnerability to SUD. Recent developmental neuroscience studies have identified microglia as regulators of synaptic plasticity.

Reversing Cocaine-Induced Plasticity with Zeta Inhibitory Peptide.

Cocaine-induced plasticity persists during abstinence and is thought to underlie cue-evoked craving. Reversing this plasticity could provide an opportunity for therapeutic intervention. Converging evidence suggest that zeta inhibitory peptide (ZIP) eliminates memories for experience-dependent behaviors, including conditioned drug associations.

Glutamate receptor interacting protein acts within the prefrontal cortex to blunt cocaine seeking.

Glutamate receptor interacting protein (GRIP) is a neuronal scaffolding protein that anchors GluA2-containing AMPA receptors to the cell membrane. GRIP plays a critical role in activity-dependent synaptic plasticity, including that which occurs after drug exposure. Given that cocaine administration alters glutamate receptor trafficking within the prefrontal cortex (PFC), a better understanding of the role of receptor trafficking proteins could lead to a more complete understanding of addictive phenotypes.

Adolescent social isolation increases cocaine seeking in male and female mice.

Childhood and adolescent adversity are associated with a wide range of psychiatric disorders, including an increased risk for substance abuse. Despite this, the mechanisms underlying the ability of chronic stress during adolescence to alter reward signaling remains largely unexplored. Understanding how adolescent stress increases addiction-like phenotypes could inform the development of targeted interventions both before and after drug use.

PKMζ in the nucleus accumbens acts to dampen cocaine seeking.

The constitutively active, atypical protein kinase C, protein kinase M-ζ (PKMζ), is exclusively expressed in the brain and its expression increases following exposure to drugs of abuse. However, the limitations of currently available tools have made it difficult to examine the role of PKMζ in cocaine self-administration and relapse. The current study demonstrates that constitutive deletion of PKMζ potentiates cue-induced reinstatement of cocaine seeking and increases both food and cocaine self-administration, without affecting cue-driven food seeking in both male and female mice.

Sex Differences in Psychiatric Disease: A Focus on the Glutamate System.

Alterations in glutamate, the primary excitatory neurotransmitter in the brain, are implicated in several psychiatric diseases. Many of these psychiatric diseases display epidemiological sex differences, with either males or females exhibiting different symptoms or disease prevalence. However, little work has considered the interaction of disrupted glutamatergic transmission and sex on disease states.

Disruption of GluA2 phosphorylation potentiates stress responsivity.

Cocaine addiction is characterized by persistent craving and addicts frequently relapse even after long periods of abstinence. Exposure to stress can precipitate relapse in humans and rodents. Stress and drug use can lead to common alterations in synaptic plasticity and these commonalities may contribute to the ability of stress to elicit relapse.

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1).

Disrupting GluA2 phosphorylation potentiates reinstatement of cocaine seeking.

Addiction is associated with changes in synaptic plasticity mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors at synapses within the nucleus accumbens. Exposure to cocaine can lead to protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and this phosphorylation event leads to the internalization of GluA2-containing AMPARs, which are calcium-impermeable. However, it is not clear whether this internalization is necessary for the expression of addictive phenotypes.