Knockdown of Lhx6 during embryonic development results in neurophysiological alterations and behavioral deficits analogous to schizophrenia in adult rats.

A decreased expression of specific interneuron subtypes, containing either the calcium binding protein parvalbumin (PV) or the neurotransmitter somatostatin (SST), are observed in the cortex and hippocampus of both patients with schizophrenia and rodent models used to study the disorder. Moreover, preclinical studies suggest that this loss of inhibitory function is a key pathological mechanism underlying the symptoms of schizophrenia. Interestingly, decreased expression of Lhx6, a key transcriptional regulator specific to the development and migration of PV and SST interneurons, is seen in human postmortem studies and following multiple developmental disruptions used to model schizophrenia preclinically.

Discrete hippocampal projections are differentially regulated by parvalbumin and somatostatin interneurons.

People with schizophrenia show hyperactivity in the ventral hippocampus (vHipp) and we have previously demonstrated distinct behavioral roles for vHipp cell populations. Here, we test the hypothesis that parvalbumin (PV) and somatostatin (SST) interneurons differentially innervate and regulate hippocampal pyramidal neurons based on their projection target. First, we use eGRASP to show that PV-positive interneurons form a similar number of synaptic connections with pyramidal cells regardless of their projection target while SST-positive interneurons preferentially target nucleus accumbens (NAc) projections.

Gestational buprenorphine exposure disrupts dopamine neuron activity and related behaviors in adulthood.

Opioid misuse among pregnant women is rapidly increasing in the United States. The number of maternal opioid-related diagnoses increased by 131% in the last ten years, resulting in an increased number of infants exposed to opioids and a subsequent increase in infants developing neonatal abstinence syndrome (NAS). The most prescribed treatment to combat maternal opioid use disorder is buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist.

Buprenorphine Exposure Alters the Development and Migration of Interneurons in the Cortex.

The misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the United States suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy.

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis.

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission.

Developmental alterations in the transcriptome of three distinct rodent models of schizophrenia.

Schizophrenia is a debilitating disorder affecting just under 1% of the population. While the symptoms of this disorder do not appear until late adolescence, pathological alterations likely occur earlier, during development in utero. While there is an increasing literature examining transcriptome alterations in patients, it is not possible to examine the changes in gene expression that occur during development in humans that will develop schizophrenia.

Stem Cells for Improving the Treatment of Neurodevelopmental Disorders.

Treatment options for neurodevelopmental disorders such as schizophrenia and autism are currently limited. Antipsychotics used to treat schizophrenia are not effective for all patients, do not target all symptoms of the disease, and have serious adverse side effects. There are currently no FDA-approved drugs to treat the core symptoms of autism.

Effect of estrous cycle on schizophrenia-like behaviors in MAM exposed rats.

Although there are clear sex differences in individuals with schizophrenia, preclinical research has historically favored the use of male rats for behavioral studies. The methylazoxymethanol acetate (MAM) model is a gestational disruption model of schizophrenia and has been reported to produce robust behavioral, neurophysiological and anatomical alterations in male rats; however, whether similar effects are observed in female rats is less well known. In this study, we characterize the behavioral, electrophysiological and molecular alterations induced by prenatal MAM administration in female rats while also examining the potential effects of the estrous cycle on schizophrenia-like behaviors.

Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1) produces a schizophrenia-like phenotype in the rat.

Adolescent cannabis use has been implicated as a risk factor for schizophrenia; however, it is neither necessary nor sufficient. Previous studies examining this association have focused primarily on the role of the cannabinoid receptor 1 (CB1R) with relatively little known about a key regulatory protein, the cannabinoid receptor interacting protein 1 (CNRIP1). CNRIP1 is an intracellular protein that interacts with the C-terminal tail of CB1R and regulates its intrinsic activity.

Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism.

Autism is a neurodevelopmental disorder characterized by disruptions in three core behavioral domains: deficits in social interaction, impairments in communication, and repetitive and stereotyped patterns of behavior or thought. There are currently no drugs available for the treatment of the core symptoms of ASD and drugs that target comorbid symptoms often have serious adverse side effects, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but converging evidence suggests that ASD involves disruptions in the inhibitory GABAergic neurotransmitter system.

Hippocampal Perineuronal Nets Are Required for the Sustained Antidepressant Effect of Ketamine.

Background: N-methyl-D-aspartate receptor antagonists, like ketamine, produce a rapid-acting and long-lasting antidepressant effect. Although the mechanism is not completely understood, ketamine is thought to preferentially target N-methyl-D-aspartate receptors on fast-spiking parvalbumin-containing interneurons. The function of parvalbumin-containing interneurons is dependent on perineuronal nets, a specialized form of extracellular matrix that surrounds these cells.

Cell-based therapies for the treatment of schizophrenia.

Schizophrenia is a devastating psychiatric disorder characterized by positive, negative and cognitive symptoms. While aberrant dopamine system function is typically associated with the positive symptoms of the disease, it is thought that this is secondary to pathology in afferent regions. Indeed, schizophrenia patients show dysregulated activity in the hippocampus and prefrontal cortex, two regions known to regulate dopamine neuron activity.

The attentional set shifting task: a measure of cognitive flexibility in mice.

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders.

Interleukin-6 attenuates serotonin 2a receptor signaling by activating the JAK-STAT pathway.

The serotonin 2A (5-HT2A) receptor and the proinflammatory cytokine, interleukin-6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior.

A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex.

Cytokines, small proteins released by the immune system to combat infection, are typically studied under inflammatory conditions. However, these molecules are also expressed in the brain in basal, nonpathological states, where they can regulate neuronal processes, such as learning and memory. However, little is known about how cytokine signaling in the brain may influence higher-order cognitive functions.

Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress.

Abnormal basal activity and stress-evoked reactivity of the hypothalamic-pituitary-adrenal (HPA) axis are often seen in depression, implicating HPA axis dysfunction as a potentially causative or exacerbating factor. Chronic stress is also a factor in depression, but it is not known what may underlie the shift from adaptive to maladaptive HPA activity over the course of chronic stress. Interleukin 6 (IL-6), a stress-inducible cytokine that signals through gp130 and IL-6Rα receptors to activate the JAK/STAT3 signaling cascade, is elevated in some subtypes of depression, and may have a modulatory effect on HPA activation, raising the possibility that IL-6 contributes to depression through effects on the HPA axis.

Chronic intermittent cold stress sensitizes neuro-immune reactivity in the rat brain.

Chronic stress contributes to many neuropsychiatric disorders in which the HPA axis, cognition and neuro-immune activity are dysregulated. Patients with major depression, or healthy individuals subjected to acute stress, present elevated levels of circulating pro-inflammatory markers. Acute stress also activates pro-inflammatory signals in the periphery and in the brain of rodents.

Zebrafish Behavior in Novel Environments: Effects of Acute Exposure to Anxiolytic Compounds and Choice of Danio rerio Line.

Zebrafish (Danio rerio) associative responses are useful for pharmaceutical and toxicology screening, behavioral genetics, and discovering neural mechanisms involved in behavioral modulation. In novel environments, zebrafish swim to tank bottoms and dark backgrounds, behaviors attributed to anxiety associated with threat of predation. To examine possible genetic effects of inbreeding and segregation on this behavior, we compared Zebrafish International Resource Center (ZIRC) AB and WIK lines to zebrafish and GloFish® from a pet store (PETCO) in two qualitatively different novel environments: the dive tank and aquatic light/dark plus maze.