Projects

INHIBITORY DEFICITS IN HUMAN AND ANIMAL MODELS OF BIPOLAR DISORDER

Individuals with Bipolar Disorder (BD) have significant difficulty in inhibiting their thoughts and behavior, which adversely impacts their ability to carry out daily activities and resume independent functioning, even when they are not actively ill. This application aims to measure inhibition across the multiple phases of BD and also to study human and animal models of the disease in parallel. Completion of this work will assist in understanding the underlying brain dysfunction of BD as well as assist in discovering and developing novel treatments.

Funding: NIMH

MONOAMINE AND HALLUCINOGEN EFFECTS ON RODENT BEHAVIOR

Despite hundreds of years of human experimentation and recent increases in the use of hallucinogens either as religious sacraments or as "Club Drugs" in recreational contexts, very little is known about the brain mechanisms underlying the behavioral effects of hallucinogens. This long-standing project uses rodent models to identify the neurobiological mechanisms of action responsible for the effects of naturally occurring hallucinogens, such as psilocybin, mescaline, and Ayahuasca, and synthetic hallucinogens such as LSD. Such information is critical to understand the consequences of the use of these compounds and to provide models of psychosis that could help identify novel therapeutic targets for neuropsychiatric disorders.

Funding: NIDA

SP4 PATHWAY IN THE MODULATION OF SENSORIMOTOR GATING AND MEMORY

The Sp4 gene, which has recently been associated with both schizophrenia and bipolar disorder, codes for an important transcription factor in brain cells that regulates the function of glutamatergic receptors involved in the cognitive impairments in psychiatric disorders. This project seeks to use animal models to elucidate molecular mechanisms related to specific cognitive abnormalities in schizophrenia, in order to aid the development of clinical interventions to prevent the dysregulation of the Sp4-glutamate pathway in human psychiatric disorders.

Funding: NIMH

STRESS AND CRF SYSTEM EFFECTS ON INFORMATION PROCESSING

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that occurs in 10- 15% of individuals exposed to a life threatening trauma. Using a mouse model of PTSD, this proposal examines the contribution of abnormalities in corticotropin releasing factor, a neurohormone released during stress, to vulnerability for development of PTSD-like symptoms and examines the efficacy of drugs that block this hormone to prevent development of PTSD-like symptoms. These studies will increase our understanding of risk factors and potential prophylactic treatments for PTSD.

Funding: NIMH

SENSITIVE AND TREATABLE PERIODS OF BRAIN-REDOX IMBALANCE IN SCHIZOPHRENIA

Schizophrenia affects millions of Americans when they reach early adulthood, but to date, there is scarce knowledge of the underlying disease processes occurring before symptoms appear. Using two neurodevelopmental mouse models of schizophrenia, this project will determine whether the period of maturation of inhibitory circuits, during early postnatal development, constitutes a sensitive period when the brain is most vulnerable to oxidative stress processes that lead to the dysfunction of specific inhibitory circuits and the appearance of schizophrenia-like symptoms in early adulthood. These studies will delineate the mechanisms inducing the increased oxidative stress in two models and the periods when they occur, and assess whether strategies that prevent oxidative stress ameliorate the neurochemical and behavioral disruptions.

Funding: NIMH

GATING AND INHIBITING IN SCHIZOPHRENIA

This application will use cross-species, translational studies to identify genes associated with deficits in specific brain-based inhibitory measures in patients with schizophrenia, and will identify the neurobiological mechanisms responsible for these deficits. The proposed studies extend the long-standing UCSD Schizophrenia Research Program work that has pioneered the use of laboratory-based biomarkers in order to better understand the clinical, cognitive, and everyday functional deficits of schizophrenia patients. By understanding the genetic and neural substrates of schizophrenia, new strong inference-based and "personalized" treatments can be identified for this devastating and costly disorder.

Funding: NIMH

The 5-choice continuous performance test: Filling the translational gap

Improving cognitive deficiencies in neuropsychiatric patients is vitally important, yet there has been limited progress in developing effective treatments. There remains a translational gap between preclinical and clinical testing, limiting the progression of compounds that succeed in humans. This project will validate the novel rodent continuous performance test of vigilance, providing a means by which positive results for compounds observed in rodents will likely succeed in man.

Funding: NIMH

Speeding ‘eureka’: Investigating the alpha 7 nicotinic receptor as a target for pharmacological augmentation of cognitive remediation in schizophrenia

The goal of these studies would be to test the hypothesis that the α7 nicotinic acetylcholine receptor (nAChR) is required for both nicotine- and varenicline-induced enhancement of reward-related learning and executive functioning. This hypothesis would be assessed using α7 nAChR knockout (KO) and wildtype (WT) littermate mice in simple and complex reward- related learning paradigms that will subsequently assess working memory span capacity and reversal learning. The results would provide immediate support for varenicline to be tested clinically as an augmentation to cognitive remediation (CR) to improve cognition in patients with schizophrenia. More importantly, these data would identify whether the α7 nAChR is a viable target for pharmacological acceleration of CR whereby more selective treatments could be developed. These studies would support my efforts to utilize preclinical testing to assist in the development of treatments to enhance cognition and functional outcome in schizophrenia. Moreover, these studies would represent a shift in approach of preclinical testing for developing such procognitive therapies, which typically focus on chronic drug treatments. It is hoped that such investigations could lead to successful treatments for the cognitive dysfunctions in schizophrenia that would impact the quality of life. Importantly, the development of such episodically used pharmacotherapies would be less vulnerable to tolerance issues and enable clinical control of medication use.

Funding: NARSAD

Psychophysiological Effects of Nicotine Use in Schizophrenia: Parallel Human and Animal Studies

Schizophrenia is a debilitating disorder affecting approximately 1% of the population. Most striking is that the first-psychotic break occurs in a subjects late-teens – early 20s. Thus, just as a subject begins to mature and become independent, they are struck with a disease that is chronic, no cure exists, and current treatments only affect psychotic symptoms, with no approved treatments for the negative symptoms or cognitive deficits. The lack of treatments for the cognitive deficits is most striking given that it is cognitive abilities are highly correlated with functional disability and may serve as a bottleneck for the acquisition and maintenance of skills necessary for independent living. Although no approved treatments for cognitive deficits exist, there is evidence suggesting that at least some patients with schizophrenia self-medicate with nicotine in order to ameliorate their attentional deficits. In this context, a very high percentage of patients smoke (40-70%), they smoke more cigarettes per day, extract more nicotine per cigarette, and preferentially select cigarettes with higher nicotine content. In order to develop novel pro-cognitive therapies for schizophrenia, we have created and validated a cross-species translational paradigm, the 5-choice continuous performance test that assesses attention and response inhibition in a consistent manner between that of humans and mice. Using this task, we propose to 1) identify regional attention-related brain response differences between patients with schizophrenia whom smoke and do not, and 2) test the effects of chronic nicotine on attentional performance in the Sp4 hypomorphic mouse model of schizophrenia. Convergent human and animal model studies have revealed that the Sp4 gene is strongly associated with cognitive abnormalities in patients with schizophrenia. Future studies will utilize identified regional abnormalities in patients to guide cerebral administration of selective nicotonic acetylcholine receptor agonists/antagonists in these mice.

Funding: CTRI