Olfactory modulation of the medial prefrontal cortex circuitry: Implications for social cognition.

Olfactory dysfunction is manifested in a wide range of neurological and psychiatric diseases, and often emerges prior to the onset of more classical symptoms and signs. From a behavioral perspective, olfactory deficits typically arise in conjunction with impairments of cognition, motivation, memory, and emotion. However, a conceptual framework for explaining the impact of olfactory processing on higher brain functions in health and disease remains lacking. Here we aim to provide circuit-level insights into this question by synthesizing recent advances in olfactory network connectivity with other cortical brain regions such as the prefrontal cortex. We will focus on social cognition as a representative model for exploring and critically evaluating the relationship between olfactory cortices and higher-order cortical regions in rodent models. Although rodents do not recapitulate all dimensions of human social cognition, they have experimentally accessible neural circuits and well-established behavioral tests for social motivation, memory/recognition, and hierarchy, which can be extrapolated to other species including humans. In particular, the medial prefrontal cortex (mPFC) has been recognized as a key brain region in mediating social cognition in both rodents and humans. This review will highlight the underappreciated connectivity, both anatomical and functional, between the olfactory system and mPFC circuitry, which together provide a neural substrate for olfactory modulation of social cognition and social behaviors. We will provide future perspectives on the functional investigation of the olfactory-mPFC circuit in rodent models and discuss how to translate such animal research to human studies.

Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.

Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory.

Cannabis is an increasingly popular and controversial drug used worldwide. Cannabis use often begins during adolescence, a highly susceptible period for environmental stimuli to alter functional and structural organization of the developing brain. Given that adolescence is a critical time for the emergence of mental illnesses before full-onset in early adulthood, it is particularly important to investigate how genetic insults and adolescent cannabis exposure interact to affect brain development and function. Here we show for the first time that a perturbation in disrupted in schizophrenia 1 (DISC1) exacerbates the response to adolescent exposure to delta-9-tetrahydrocannabinol (Δ(9)-THC), a major psychoactive ingredient of cannabis, consistent with the concept that gene-environment interaction may contribute to the pathophysiology of psychiatric conditions. We found that chronic adolescent treatment with Δ(9)-THC exacerbates deficits in fear-associated memory in adult mice that express a putative dominant-negative mutant of DISC1 (DN-DISC1). Synaptic expression of cannabinoid receptor 1 (CB1R) is down-regulated in the prefrontal cortex, hippocampus, and amygdala, critical brain regions for fear-associated memory, by either expression of DN-DISC1 or adolescent Δ(9)-THC treatment. Notably, elevation of c-Fos expression evoked by context-dependent fear memory retrieval is impaired in these brain regions in DN-DISC1 mice. We also found a synergistic reduction of c-Fos expression induced by cue-dependent fear memory retrieval in DN-DISC1 with adolescent Δ(9)-THC exposure. These results suggest that alteration of CB1R-mediated signaling in DN-DISC1 mice may underlie susceptibility to detrimental effects of adolescent cannabis exposure on adult behaviors.

Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging.

Imaging of the human brain has been an invaluable aid in understanding neuropsychopharmacology and, in particular, the role of dopamine in the striatum in mental illness. Here, we report a study in a genetic mouse model for major mental illness guided by results from human brain imaging: a systematic study using small animal positron emission tomography (PET), autoradiography, microdialysis and molecular biology in a putative dominant-negative mutant DISC1 transgenic model. This mouse model showed augmented binding of radioligands to the dopamine D2 receptor (D2R) in the striatum as well as neurochemical and behavioral changes to methamphetamine administration. Previously we reported that this model displayed deficits in the forced swim test, a representative indicator of antidepressant efficacy. By combining the results of our two studies, we propose a working hypothesis for future studies that this model might represent a mixed condition of depression and psychosis. We hope that this study will also help bridge a major gap in translational psychiatry between basic characterization of animal models and clinico-pharmacological assessment of patients mainly through PET imaging.

The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder.

Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. This study shows the miR-124-3p-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered the upregulation of miR-124-3p in neuronal cells and the postmortem prefrontal cortex from both SZ and BP patients. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124-3p in the medial prefrontal cortex. We demonstrated that the upregulation of miR-124-3p increases GRIA2-lacking calcium-permeable AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.

Better understanding of mechanisms of schizophrenia and bipolar disorder: from human gene expression profiles to mouse models.

The molecular mechanisms of major mental illnesses, such as schizophrenia and bipolar disorder, are unclear. To address this fundamental question, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Development of unbiased high-throughput approaches, such as microarray, RNA-seq, and proteomics, have supported and facilitated this endeavor. In addition to genes directly involved in neuron/glia signaling, especially those encoding for synaptic proteins, genes for metabolic cascades are differentially expressed in the brains of patients with schizophrenia and bipolar disorder, compared with those from normal controls in DNA microarray studies. Here we propose the importance and usefulness of genetic mouse models in which such differentially expressed molecules are modulated. These animal models allow us to dissect the mechanisms of how such molecular changes in patient brains may play a role in neuronal circuitries and overall behavioral phenotypes. We also point out that models in which the metabolic genes are modified are obviously untested from mental illness viewpoints, suggesting the potential to re-address these models with behavioral assays and neurochemical assessments.

Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice.

D-Amino acid oxidase (DAAO) catalyzes the oxidative deamination of D-amino acids including D-serine, a full agonist at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor. To evaluate the significance of DAAO-mediated metabolism in the pharmacokinetics of oral D-serine, plasma D-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. Although D-serine levels were rapidly diminished in wild-type mice (t(½) = 1.2 h), sustained drug levels over the course of 4 h (t(½) > 10 h) were observed in mice lacking DAAO. Coadministration of D-serine with 6-chlorobenzo[d]isoxazol-3-ol (CBIO), a small-molecule DAAO inhibitor, in wild-type mice resulted in the enhancement of plasma D-serine levels, although CBIO seems to have only temporary effects on the plasma D-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in the clearance of D-serine from the systemic circulation. Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma D-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia.

Sex-specific involvement of the Notch-JAG pathway in social recognition.

Under the hypothesis that olfactory neural epithelium gene expression profiles may be useful to look for disease-relevant neuronal signatures, we examined microarray gene expression in olfactory neuronal cells and underscored Notch-JAG pathway molecules in association with schizophrenia (SZ). The microarray profiling study underscored JAG1 as the most promising candidate. Combined with further validation with real-time PCR, downregulation of NOTCH1 was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile of Notch1+/- mice. We found a specific impairment in social novelty recognition, whereas other behaviors, such as sociability, novel object recognition and olfaction of social odors, were normal. This social novelty recognition deficit was male-specific and was rescued by rapamycin treatment. Based on the results from the animal model, we next tested whether patients with psychosis might have male-specific alterations in social cognition in association with the expression of NOTCH1 or JAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression of JAG1 and a face processing measure only in male patients. The expression of JAG1 was not correlated with any other cognitive and symptomatic scales in all subjects. Together, although we acknowledge the pioneering and exploratory nature, the present work that combines both human and animal studies in a reciprocal manner suggests a novel role for the Notch-JAG pathway in a behavioral dimension(s) related to social cognition in psychotic disorders in a male-specific manner.

Neurodevelopmental Factors in Schizophrenia.

The onset of schizophrenia is usually in late adolescence or early adulthood. However, accumulating evidence has suggested that the disease condition is an outcome of gene-environment interactions that act in neural development during early life and adolescence. Some children who later develop schizophrenia have early developmental and educational and social challenges. Some patients with schizophrenia have an abundance of nonspecific neurologic soft signs and minor physical anomalies. Adolescence is a sensitive period of increased neuronal plasticity. It is important to consider early detection and intervention from the prodromal stage to early disease to prevent its devastating long-term consequences.