Hippocampus-associated cognitive impairments are a common, highly conserved symptom of both schizophrenia (SCZ) and bipolar disorder (BPD). Although the hippocampus is likely an impacted region in SCZ/BPD patients, the molecular and cellular underpinnings of these impairments are difficult to identify. An emerging class of mouse models for these psychiatric diseases display similar cognitive impairments to those observed in human patients. The hippocampi of these mice possess a conserved pathophysiological alteration; we term the ‘immature dentate gyrus' (iDG), characterized by increased numbers of calretinin-positive immature neuronal progenitors, a dearth of calbindin-positive mature neurons and (often) constitutively increased neurogenesis. Although these models provide a link between cellular dysfunction and behavioral alteration, limited translational validity exists linking the iDG to human pathophysiology. In this study, we report the initial identification of an iDG-like phenotype in the hippocampi of human SCZ/BPD patients. These findings suggest a new motif for the etiology of these diseases and link an emerging class of mouse models to the human disease condition.

Norepinephrine (NE) is widely implicated in opiate withdrawal, but much less is known about its role in opiate-induced locomotion and reward. In mice lacking dopamine beta-hydroxylase (DBH), an enzyme critical for NE synthesis, we found that NE was necessary for morphine-induced conditioned place preference (CPP; a measure of reward) and locomotion. These deficits were rescued by systemic NE restoration. Viral restoration of DBH expression in the nucleus tractus solitarius, but not in the locus coeruleus, restored CPP for morphine. Morphine-induced locomotion was partially restored by DBH expression in either brain region. These data suggest that NE signaling by the nucleus tractus solitarius is necessary for morphine reward.

An increasing body of evidence suggests that alterations in neurogenesis and oxidative stress are associated with a wide variety of CNS diseases, including Alzheimer’s disease, schizophrenia and Parkinson’s disease, as well as routine loss of function accompanying aging. Interestingly, the association between neurogenesis and the production of reactive oxidative species (ROS) remains largely unexamined. The adult CNS harbors two regions of persistent lifelong neurogenesis: the subventricular zone and the dentate gyrus (DG). These regions contain populations of quiescent neural stem cells (NSCs) that generate mature progeny via rapidly-dividing progenitor cells. We hypothesized that the energetic demands of highly proliferative progenitors generates localized oxidative stress that contributes to ROS-mediated damage within the neuropoietic microenvironment. In vivo examination of germinal niches in adult rodents revealed increases in oxidized DNA and lipid markers, particularly in the subgranular zone (SGZ) of the dentate gyrus. To further pinpoint the cell types responsible for oxidative stress, we employed an in vitro cell culture model allowing for the synchronous terminal differentiation of primary hippocampal NSCs. Inducing differentiation in primary NSCs resulted in an immediate increase in total mitochondria number and overall ROS production, suggesting oxidative stress is generated during a transient window of elevated neurogenesis accompanying normal neurogenesis. To confirm these findings in vivo, we identified a set of oxidation-responsive genes, which respond to antioxidant administration and are significantly elevated in genetic- and exercise-induced model of hyperactive hippocampal neurogenesis. While no direct evidence exists coupling neurogenesis-associated stress to CNS disease, our data suggest that oxidative stress is produced as a result of routine adult neurogenesis.

N-methyl-D-aspartate (NMDA) receptor antagonists can elicit symptoms in humans that resemble those seen in schizophrenic patients. Rodents manifest locomotor and stereotypic behaviors when treated with NMDA receptor antagonists such as phencyclidine (PCP) or dizocilpine maleate (MK-801); these behaviors are usually associated with an activated dopamine system. However, recent evidence suggests that increased glutamatergic transmission mediates the effects of these NMDA receptor antagonists. The role of dopamine in PCP-and MK-801-induced behavior (eg hyperlocomotion) remains unclear. We used dopamine-deficient (DD) mice in which tyrosine hydroxylase is selectively inactivated in dopaminergic neurons to determine whether dopamine is required for the locomotor and molecular effects of PCP and MK-801. DD mice showed a similar increase in locomotor activity and c-fos mRNA induction in the striatum in response to these NMDA receptor antagonists as control mice. Restoration of dopamine signaling in DD mice enhanced their locomotor response to PCP and MK-801. Administration of LY379268, a group II metabotropic glutamate receptor agonist that inhibits glutamate release, blocked PCP-and MK-801-induced hyperlocomotion in both DD and control mice. These results suggest that glutamate, rather than dopamine, is required for the locomotor and molecular effects of NMDA receptor antagonists, but that glutamate and dopamine can act cooperatively.