Projects

PI: Adam L. Halberstadt; Co-I: Susan Powell, Mark Geyer

New Psychoactive Substances (NPS) are substances designed to mimic the effects of controlled substances and other abused drugs. Although designer drugs are not a new phenomenon, the number and availability of NPS is unprecedented and has increased dramatically over the last 5 years. NPS represents a growing international public health problem, with hundreds of drugs currently being marketed online and new substances appearing every week. The PI is involved in a large collaborative effort to rapidly identify and characterize new NPS, define their structure-activity relationships (SAR), and determine the mechanisms of their behavioral and toxic actions. Experimental approaches employed include spectroscopic techniques (NMR, LC-HR-MSn), receptor assays, rodent behavioral models, and assessment of drug metabolism and disposition.

Funding Source: NIH/NIEHS R01 ES025585-01
Multi-PI: Susan Powell, Marga Behrens, Joe Ecker

Human genetics and animal models suggest that alterations in synapse formation and maintenance may be fundamental to the etiology of ASD, and recent human exome-profiling studies suggest transcription and chromatin remodeling functions may be affected. Epigenetic regulation of gene transcription, including through developmentally dynamic and cell type-specific patterns of DNA methylation, is a plausible mechanism mediating long-term environmental contributions to ASD. Environmental impacts on the overall configuration of DNA methylation (methylome) may lead to aberrant silencing or activation of genes involved in brain circuit maturation, with subsequent functional and behavioral consequences. Recently, the first analysis of whole-genome single-base resolution methylome maps of developing frontal cortex in mice and humans revealed extensive epigenomic reconfiguration during development from fetal to young adult. We identified multiple dynamic features of brain cell DNA methylation, including accumulation of non-CG methylation in neurons during the period of synaptogenesis. These results point to a potential role of the neuronal methylome in healthy development of neural circuits that could be particularly vulnerable to pathological disruption, e.g. in response to environmental exposures and/or genetic mutations. This proposal leverages these results together with preliminary data showing dynamic changes methylation during the transition between embryonic and early life in mouse brain to test the hypothesis that alteration of specific forms of DNA methylation are involved in the origins of ASD. Aim 1 will produce genome-wide, single-base resolution methylome maps in the two major neuronal populations in the frontal cortex i.e. excitatory and inhibitory neurons, in a well-established model of ASD, the maternal immune activation (MIA) model. Additionally, to test the additive effects of environmental exposures in a compromised gestation, Aim 2 will expose the MIA animals to the environmental toxin PBDE. Finally, Aim 3 will analyze the methylome changes produced by MIA in animals that are deficient for the autism risk gene Shank3 to test for gene x environment interactions. The transcriptional consequences of methylome changes will be assessed by RNA-Seq for each neuronal population at each time-point during development, and long-term behavioral consequences will be assessed through a battery of behavioral tests relevant to ASD. We will use new, sophisticated computational analysis procedures to integrate diverse and large-scale empirical data sets to provide a powerful and stringent test of our hypotheses.

Funding Source: NIH/NIMH R21 MH122838-01
PIs(s): Susan Powell (contact), Samuel Barnes

Autism spectrum disorder (ASD) is characterized by social and communication deficits as well as restricted, repetitive behaviors (RRBs). RRBs include "lower order" motor stereotypies such as body rocking and hand waving as well as more elaborate, compulsive behaviors or "higher order" RRBs such as checking and hoarding and insistence on sameness. Although RRBs, along with social and communicative deficits, constitute the triad of symptoms essential to the diagnosis of autism, RRBs have been surprisingly understudied. The extant question in the field is: what neural circuits mediate RRBs and how might these circuits be altered in ASD and thus targeted for treatment? Insistence on sameness behavior can be measured in tasks of cognitive flexibility using reversal learning paradigms. Individuals with ASD have specific deficits in reversal learning paradigms that use a probabilistic reinforcement schedule, which can be tested in mice using similar cross-species paradigms to probe neural circuitry and treatments. Because prenatal inflammation is a risk factor for autism and other neurodevelopmental disorders, we and others have conducted studies of maternal immune activation (MIA) in model organisms. In addition to social deficits, MIA mice have deficits in probabilistic reversal learning similar to that observed in ASD. Disruptions in frontal cortex function, particularly orbito-frontal cortex (OFC) and striatum lead to deficits in cognitive flexibility. Preliminary data from our lab show that OFC->dorsal medial striatum (DMS) circuit activation disrupts probabilistic reversal learning in a manner consistent with ASD. Intriguingly, structural and functional abnormalities of the OFC are evident in ASD, which may contribute to RRBs. Thus, we hypothesize that probabilistic reversal learning deficits in MIA mice are due to overactivation of OFC-DMS circuit and that inhibiting this circuit will ameliorate the deficits. Aim 1 studies will test whether optogenetic activation of OFC->DMS glutamate projections will exacerbate RRBs in MIA mice and/or replicate RRBs in control mice. Channelrhodopsin (ChR2, a blue light-gated cation channel) will be expressed via the CamKII promoter selectively in glutamate neurons in the OFC. Fiber optic probes will be implanted in the DMS to stimulate terminals from the OFC during the reversal phase of the task. Aim 2 studies test whether OFC-DMS circuit inhibition ameliorates cognitive flexibility deficits in MIA mice. Specifically, a CamKII promoter-driven halorhodopsin (eNpHR3.0, a green light-gated chloride ion pump) will be infused into the OFC, and stimulation of fiber optic probes in the DMS will test whether optogenetic inhibition of OFC->DMS neurons attenuates cognitive flexibility deficits in MIA mice. Because both ASD and MIA are associated with decreased GABA function in frontal cortex, Aim 3 studies test whether enhancing OFC GABA transmission ameliorates cognitive flexibility deficits in MIA mice. These experiments will provide evidence for a specific circuit involved in RRBs in MIA and a possible remediation through inhibition of the circuit and potential treatment approaches for RRBs in ASD.
 

Funding Source: VA Merit award
PI: Susan Powell; Co-I: Samuel Barnes, Dhakshin Ramanathn

Patients with schizophrenia are some of the most ill in our society. The inadequacy of treatment response and myriad side effects of current medications makes long-term care and medication adherence difficult.  Hence, better treatment of patients with psychotic disorders will greatly improve their overall quality of life and long-term care. Recent evidence suggests that social isolation or withdrawal may contribute to the emergence of psychiatric illness, or be a precipitating factor. For example, social withdrawal in schizophrenia occurs prior to symptoms of psychosis and continued social decline predicts conversion to psychosis. Individuals with schizophrenia show disruptions in frontal cortex and hippocampal circuitry, which contribute to negative symptoms and cognitive deficits. Cognitive deficits are particularly debilitating and remain undertreated with current antipsychotic medications. Based on the course of illness it is likely that the severity of social withdrawal/isolation contributes to the neuropathology in schizophrenia; however, the mechanism through which this progression occurs is not known. Because of ongoing deterioration in symptoms and better prognosis with early therapeutic interventions, there is a need to identifying potential risk factors, prodromal symptoms, and biomarkers to help screen military personnel at risk for serious mental illness and provide opportunities for early intervention. The goals of the proposed studies are (1) to determine the impact of social isolation (SI) in rodents on frontal cortex and hippocampal circuitry and behaviors relevant to schizophrenia (e.g. deficits in cognitive flexibility and sensorimotor gating) and (2) identifying biomarkers predictive of susceptibility, and (3) develop more efficacious early interventions for neuropsychiatric disorders, particularly schizophrenia. Aim 1 studies assess the contribution of glutamate and GABA function in cortex and hippocampus to the development of cognitive deficits in socially isolated rats. Studies examine the progression of both cognitive deficits and alterations in markers of excitatory and inhibitory neurons via immunohistochemistry and glutamatergic neuronal activity via in vivo fiber photometry. Aim 2 studies use optogenetics to determine whether neuromodulation of orbitofrontal cortex (OFC) to dorsomedial striatum (DMS) glutamate projections can remediate cognitive deficits in socially isolated rats. Aim 3 studies examine whether early interventions with a metabotropic glutamate receptor agonist, LY379268, to decrease glutamate signaling can prevent the development of cognitive dysfunction associated with social isolation. These preclinical studies will provide a better understanding of the impact of social isolation on neural circuitry and cognitive behavior and identify potential therapeutic targets for future studies in Veterans.
 

TBI

Funding Source: VA SAN DIEGO HEALTHCARE SYSTEM, BLR&D BX004312-01

Multi-PI: Risbrough, V; Rissman R.

Traumatic brain injury (TBI) is a signature injury of OIF/OEF Veterans. More than 360,000 armed service members sustained TBI during combat and training from 2000 to 2016. There is currently no diagnostic biological marker for TBI nor can current diagnostic tools identify individuals at greatest risk for chronic neurological and subsequent functional impairments after TBI. Neuronally-derived exosomes (NDEs) obtained from peripheral blood may be a powerful tool to develop accessible CNS based biomarkers associated with neuronal dysfunction, particularly in relation to long-term brain injury and neurodegeneration. Our recently published work demonstrates that neuropathological proteins (e.g beta amyloid, Aß, and tau) within NDEs can predict conversion from mild cognitive impairment to Alzheimer's Disease (AD) while plasma levels do not. Studies of NDEs are now being tested as companion biomarkers in AD clinical trials to help reduce screen fail rates and increased enrollment. We have recently found that cytoskeletal and synaptic proteins are also abnormal in deployment related TBI patients >3 mo after TBI. Specifically, both Aß and neurogranin are altered in plasma NDEs from participants who experienced a deployment-related TBI. Taken together, our data support the hypothesis that plasma NDEs may be a powerful tool to identify accessible and CNS-specific protein biomarkers for TBI. NDEs are also enriched for short length "micro" RNA (miRNA) cargo. Each miRNA can regulate protein expression from hundreds of target messenger RNAs, providing an efficient mechanism to exert genome-wide regulation and simultaneously affect several cellular pathways. miRNAs confer tissue specificity and have recently emerged as potential biomarkers and therapeutic targets for neurodegeneration. Hence, identification of CNS-specific miRNAs associated with NDEs may provide a window to the pathogenic processes in chronic TBI for future intervention. We hypothesize that proteins related to neurodegeneration within NDEs, such as Aß, as well as miRNAs associated with NDEs have the potential to be biomarkers of TBI and associated symptoms. To test this hypothesis we will leverage our prospective longitudinal study of combat deployment effects in >1200 Marines, of which 176 experienced mild/moderate deployment-related TBI. This study collected physical and mental health, neurocognitive performance and blood samples 1 mo before and 4-6 mo after a combat deployment to Afghanistan. We will use 150 TBI samples with 150 samples of matched controls with no TBI history to complete 2 aims. Aim 1 will examine utility of cytoskeletal and neuronal proteins in NDEs to identify TBI in addition to persistence of post-concussive symptoms and cognitive decline. Candidate neurodegenerative proteins include tau, Aß, neurogranin, neurofilament light chain and calpain-cleaved αII-spectrin N-terminal fragment. Studies will also leverage these prospective samples to examine if change in NDE proteins from pre-and post injury reflects symptom change, providing potential causal inferences for these proteins in the pathogenic process of TBI. Aim 2 will use an unbiased discovery approach to identify novel miRNAs associated with TBI and associated symptoms and neurocognitive decline. Small RNA sequencing will be conducted on exosomal RNA. miRNA associated with TBI will be validated using RT-qPCR and replicated in an independent sample set. Top candidates will be examined for changes pre and post injury to understand the contribution of these markers to the pathogenic process after injury. This study has strong potential to provide accessible, quantitative biomarkers for TBI and associated symptoms, as well as identify potential functional targets for intervention.

Funding Source: NIAAA R01 AA026560

Principal Investigator(s): Risbrough, V; Der-Avakian A

RFA-AA-17-016 states that "Studies examining alcohol related behaviors in current models of PTSD and potentially in novel animal models of PTSD are sought". Animal models of PTSD are on the cutting edge of exploiting individual differences to understand mechanisms underlying resilience and susceptibility to psychopathology. Validated models of PTSD recapitulate the prevalence of PTSD in trauma-exposed individuals (~15-30% depending on trauma). We will use 2 well-validated animal models of PTSD, social defeat stress and predator stress, to understand in what biological contexts trauma and subsequent enduring stress response provokes drinking behavior. Predator stress models the enduring effects of a severe single traumatic event while social defeat stress models effects of chronic physical and emotional stress. Both models produce variance in enduring response rates to trauma exposure, (30-50% of animals exhibit prolonged behavioral and neurobiological change), providing etiological validity for PTSD. We propose to examine if two highly translatable markers of trauma-symptom development, sleep disturbance and increased peripheral immune signaling, predict development and/or maintenance of drinking after stress in rodents. This approach addresses the RFA mandate to "identify biomarkers that will predict transition of PTSD to comorbid PTSD-alcohol misuse." The goal is to (1) develop robust cross-species biomarkers of long term-trauma effects associated with increased alcohol consumption and (2) identify biomarkers that are predictive for treatment response. We will test the hypothesis that sleep and inflammation abnormalities after trauma predict increased drinking and treatment response. To test this hypothesis we will use a large (N=200/model) prospective, longitudinal design based on clinical research approaches. This strategy enables use of sophisticated statistical models to identify biological predictors of drinking behavior. We will assess clinical relevance by comparing these findings to humans by leveraging our clinical database of a prospective, longitudinal study of trauma in active duty service members (N=2600). This database includes data on trauma, PTSD symptoms, alcohol dependence, sleep and peripheral inflammation both before and after a combat deployment. Once validated, sleep and immune biomarkers identified in our animal models and validated in humans can be used to screen for prophylactic and therapeutic treatment effects of novel pharmacotherapies.

Funding Source: Department of Defense W81XWH15
Principal Investigator(s): Risbrough, V (Corresponding PI); Drummond, Sean (Site PI)

Posttraumatic stress disorder (PTSD) is common among Service Members and military Veterans. One defining feature of PTSD is impairments in fear and fear inhibition processes. In PTSD, fear conditioning occurs where cues in the environment lead people to predict imminent threat or danger. Fear inhibition includes both fear extinction and safety learning. Fear extinction is the process of learning that previous "threat" cues are no longer dangerous so the person no longer responds to those cues with fear. Safety learning is the opposite of fear learning, where the individual learns that certain cues in the environment predict safety or absence of danger. It is believed that learning fear inhibition, as well as retaining that learning over time, are critical to preventing PTSD after trauma exposure and recovering from PTSD once it develops. Unfortunately, sleep problems, particularly interruptions in certain stages of sleep such as rapid eye movement (REM) sleep (the stage of sleep in which we dream), have been shown to impair peoples' ability to retain fear inhibition, possibly making it harder to recover from trauma. This disruption in fear inhibition is of great concern because sleep problems are one of the core features of PTSD, and thus may be involved in the maintenance of PTSD symptoms.
While past studies strongly suggest REM sleep is necessary for fear inhibition, no studies have looked specifically at the types of sleep disruption seen in military personnel at risk for PTSD. There are two factors likely to disrupt normal REM sleep in military populations: REM fragmentation and circadian misalignment. REM fragmentation (frequent interruptions in REM sleep) can occur either due to generally disrupted and inconsistent sleep patterns seen during training and deployment or from insomnia and nightmares typical in the immediate aftermath of trauma exposure. Circadian misalignment occurs when one attempts to sleep outside of one's biological night. This misalignment could occur due to frequent travel across time zones, initiation of missions within days of entering a new time zone, and/or as a result of frequent nocturnal missions or other shift work. These operational realities would be expected to impair fear inhibition processes. 
The primary goals of this study are: a) to determine if these two common ways that REM sleep becomes disrupted in military operations impair fear inhibition processes in ways consistent with impairments seen in PTSD; and b) test if increasing REM sleep can prevent impaired fear inhibition in the face of circadian misalignment. We will test REM Fragmentation (Aim 1) and Circadian Misalignment (Aim 2) methods of disrupting REM sleep. We predict each method will lead to decreased quantity and/or quality of REM sleep, and this REM disruption will, in turn, impair fear inhibition.  Sixty participants will take part in Aim 1 in the San Diego Veterans Affairs Hospital and 60 will take part in Aim 2 at Monash University.
 

Funding Source: NIMH P50 Silvio Conte Center P50MH096889
Principal Investigator(s): Baram, T (Center PI), Risbrough, V; Baker DG Project 4 PIs.

Mental illness, including PTSD, depression and suicide afflict >20% of adolescents and young adults, with tremendous social and fiscal costs. Late adolescent / young adult service members facing combat are at significant risk for trauma-related disorders, constituting an ideal population to test predictions of the overarching hypothesis driving this Conte Center: that early-life fragmentation/unpredictability (FRAG) is associated with early manifestations of anhedonia via alterations in pleasure/reward circuits, which presage increased risk for psychopathology in adulthood. Our studies aim to provide evidence for a novel, unsuspected risk factor for psychopathology in a vulnerable population. 
We will leverage a large prospective and longitudinal cohort of late-adolescents/young adults: recruited in the Marine Resiliency Study (MRS). This study assessed anhedonia in service members at pre-deployment and 3-6 months after deployment. For this project, we will re-contact MRS participants to test the following hypotheses: 

1. that FRAG--in addition to, and independent from, other established factors such as early-life adversity--predict anhedonia during late adolescence / early adulthood.
2. that early-life FRAG and subsequent anhedonia in early adolescence/early adulthood increase the risk for trauma-related psychopathology. The latter prediction is strongly supported by our preliminary data indicating that pre-deployment anhedonia predicts increased PTS symptoms and increased prevalence for PTSD ~1 year later (N=1972).  This aim will probe the clinical relevance of the center-proposed FRAG and anhedonia risk factors.
3. that FRAG and anhedonia promote trauma-related psychopathology via aberrant pleasure-reward circuitry. We test if individuals endorsing current PTS symptoms and these earlier "risk" factors (FRAG and Anhedonia during adolescence/young adulthood) will exhibit aberrant reward circuit structure and function compared to individuals with PTS symptoms that do not endorse these risk factors.  Defining trajectories from early life to adulthood, this integrated approach will advance our understanding of early-life signals, especially FRAG in anhedonia and alterations in pleasure/reward circuits which presage increased risk for psychopathology in adulthood.

Funding:  Center of Excellence for Stress and Mental Health
Directors:  Risbrough, V & Nievergelt, C

The CESAMH biorepository was developed to leverage ongoing studies in PTSD/TBI conducted by CESAMH investigators and its affiliates in PTSD/TBI.  The biorepository collects tissue samples and symptom data to support studies in biological markers of PTSD/TBI and their comorbidities as well a markers of treatment response.  The biorepository focuses on longitudinal studies and prioritizes providing infrastructure to collect samples in clinical treatment studies.  The repository collects whole blood, plasma, urine and saliva in addition to conducts an ex vivo lipopolysaccharide challenge test at 0, 3 and 6 mo time points.  Data and tissue samples can be accessed through a biorepository board vetting process with priority to VA investigators.
 

Funding:  National Institute for Drugs of Abuse
PIs:  Jared W. Young & William Perry

Cannabis is used by more than half of all people with bipolar disorder (BD), which may increase with continued legalization across the United States. Some but not all of the deleterious cognitive effects of cannabis are likely exaggerated in people with BD, given that the brain's endocannabinoid (ECB) system affects the function of dopaminergic (DA) circuitry, which is thought to be dysregulated in BD. For example, administration of the cannabinoid1 (CB1) receptor agonist delta-9-tetrahydrocannabidiol (THC) - the primary active ingredient in cannabis - increases DA release in the striatum. This effect is especially problematic in BD individuals who have reduced expression of the dopamine transporter (DAT), the mechanism driving homeostatic regulation of DA levels. On the other hand, cannabidiol (CBD) is the other major ingredient of cannabis and does not increase DA levels, so cannabis containing high CBD may not be as deleterious. A better understanding of the consequences of chronic cannabis use on critical cognitive functions and ECB/DA neurochemistry in BD could further the development of treatments for BD and substance use disorders. The proposed use of cross-species measures and parallel studies in both humans and rodents enables a more nuanced understanding of both the neurobiology and clinical applicability of the ECB system in BD. Aim 1 will determine the effects of chronic cannabis use on cognitive functions relevant to BD, in chronic cannabis users and non-users compared to healthy comparison (HC) participants. A battery of cognitive and behavioral tests that measure domains such as arousal, inhibitory control, feedback-based decision making, reward preference, and temporal perception will be administered. Aim 2 will identify the effects of acute exposure to controlled doses of THC and CBD on cognition and determine the resulting levels of endogenous cannabinoids such as anandamide (AEA) and the DA metabolite homovanillic acid (HVA) via lumbar puncture. Infrequent cannabis-using BD and HC participants will be randomized to receive one of 3 preparations of placebo, THC, or THC/CBD and will be tested on the cognitive-behavioral battery. Aim 3 will determine the interactive effects of reduced DAT function (a validated mouse model for BD) and THC/CBD treatment (acute, chronic, and withdrawal states) on cognition, neuropathology, plus ECB, DA receptor, and AEA expression in mice. The rodent behavioral tests have direct translational applicability to the human tests described above. It is hypothesized that BD participants and mice with reduced DAT expression will show interactive and additive effects of chronic cannabis use both on cognition and on ECB and HVA levels, due to complex interactions between the ECB and DA systems. Acute THC exposure may decrease arousal and improve temporal perception in BD and KD mice but impair inhibition and decision making, whereas CBD will not exert as deleterious effects. In addition to shedding new light on the neurobiology of BD and cannabis use disorder, these studies may inform how pharmacological manipulation of the ECB system can become a novel approach for treating BD.
 

Funding:  National Institute for Mental Health
PI: Jared W. Young

There has been a fundamental failure to translate preclinically-supported compounds into clinically-approved treatments. This failure generally reflects the profound differences between phenomenon assessed in the laboratory and those targeted in the clinic. Behavioral similarity is not enough to suggest translation. For novel treatments to emerge, they will require animal models with cross-species consistency. Hence, there is a critical need for: i) neurophysiological biomarkers of behaviors relevant to domains affected in psychiatric patients that; ii) can be conducted across species; and iii) that are altered by drug treatment. Such biomarkers would prove stronger evidence that effective preclinical pharmacological manipulations could be effective clinical treatments. We developed the 5-choice continuous performance test (5C-CPT) to quantify cognitive control and response inhibition for use in rodents and humans. We also developed a probabilistic learning (PL) task for mechanistic understanding of reward learning across species. New endeavors here include the progressive ratio breakpoint procedure (PRBP), a task first developed to quantify motivation from physical effort and a rodent cognitive effort task (CET) both of which have recently been reverse-translated for human testing. In addition, action selection/preference-based decision making can be measured across species using the risky gains task (RGT), which quantifies responding to positive vs. negative feedback on a trial-by-trial basis. The UH2 component of this application (Specific Aim 1) will use electrophysiological biomarkers to test the following hypothesis across species: 5C-CPT 1A) Non-target (nogo) stimuli response levels (response inhibition) will inversely correlate with larger frontal event-related potential (ERP) components (e.g. P3a) and 1B) Parietal beta activity will correlate with the sensitivity index measure of cognitive control. PL 2A) the Reward Positivity ERP component, which scales with the degree of positive prediction error, will vary in strength according to probability ratio (80/20>70/30>60/40) and 2B) the strength of the Reward Positivity will correlate with the % correct within each ratio block. PRBP 3) Physical effort will be linked to frontal alpha power; CET 4) Hard cognitive effort choices will be linked to ACC activation as measured by frontal midline theta power. RGT 5A) A stronger mid-frontal theta oscillatory component (Feedback-Related Negativity) will correlate with shifting choices after punishment feedback while 5B) Parietal delta power (e.g. P3) locked to the imperative cue will correlate with the likelihood of staying at the same choice after reward Tasks fulfilling these hypotheses in both mice and humans will then move onto the UH3 component (Specific Aim 2) which will test whether elevating frontal dopamine levels via tolcapone treatment will influence behavior and neurophysiological markers during these tasks. For example, we would hypothesize that tolcapone would induce stronger frontal late ERPs and reduced response inhibition in the 5C-CPT, or increased ACC activation and hard-choice preference in the CET.
 

PI:  Jared W. Young, CoI: Susan B. Powell

Psychiatric conditions such as schizophrenia, bipolar disorder, or depression, do not arise from a single contribution.  Both genetic and environmental conditions contribute to the rise of such conditions.  Some environmental factors play such an early role that they can interfere with placental morphology and thus modulate the neurodevelopmental trajectories of offspring.  This work will determine the mechanistic cause and impact of such environmental insults as well as identify potential genetic factors that confer both susceptibility and resilience to these factors.  Focus is placed particularly on cognitive and motivational processes of behaviors known to be affected in patients and vitally important for their societal functioning. 

PIs: Jared W. Young & Arthur L. Brody
Funding:  National Institute for Drugs of Abuse

People with HIV-1 infection smoke at higher rates (40%) than the general population (16%), with non-HIV smokers showing a greater ability to quit. Given the movement of HIV infection from a `fatal' to `chronic' disease, increased smoking rates may negatively impact long-term health outcomes. Understanding why rates are so high remains critical to aiding quit attempts. Given that HIV infection results in inflammation, and nicotine (the primary psychoactive ingredient of tobacco) reduces inflammation, people with HIV may smoke as a means to medicate symptoms. Nicotine exerts numerous effects including improvement in cognitive domains that are deficient in people with HIV. Alternatively, those with HIV may continue to smoke because they experience greater withdrawal effects than the general population. This project will investigate these potential mechanisms. Aim 1 will determine the impact of current smoking on cognitive functioning and use a positron emission tomography (PET) marker to determine neuroinflammation in HIV positive and healthy participants (n=21/gp). Reverse-translated tasks and the NIH Toolkit will characterize the potential positive benefits of smoking satiety in HIV positive participants. Further, current microglia-based neuroinflammatory markers will be determined and compared to cognitive performance. While informative, this cross-sectional analysis will not be able to determine directionality of effects. Hence, Aim 2 will determine directionality of chronic nicotine & withdrawal effects on cognition and neuroinflammation in mice that express the HIV-associated gp120 protein and their wildtype (WT) littermates. In Expt. 1, the effects of chronic nicotine on cognition will be examined using rodent-based tasks from Aim 1. In addition, similar neuroinflammatory markers will be investigated at each stage of treatment (baseline-, acute-, chronic-, and withdrawal-induced effects). In Expt. 2, this work will be repeated in the gp120-mouse model of HIV to determine nicotine's potential interactive effects with this HIV- relevant protein. Finally, Expt. 3 will include antiretroviral treatment (ART; an integrase inhibitor) to determine potential three-way interactions of nicotine, gp120 protein, and ART on cognition and neuroinflammation. Hence, the potential for synergistic enhancement (during nicotine treatment) and deficits (during nicotine withdrawal) on each factor will be determined. Finally, potential changes in dopamine and nicotinic receptor expression will be examined. Hence, these studies will establish the cognitive profile of deficits related to HIV and comorbid cigarette/nicotine use, as well as their link to neuroinflammation. More importantly, using cross- species relevant testing, the `chicken or the egg' conundrum will be answered as to whether those with HIV smoke more and have greater difficulty quitting because of a specific remediation of such deficits with nicotine and/or greater deleterious effects during withdrawal respectively. Neuropathology studies will also help identify potential targets for treatment development and smoking cessation aids to improve the lives of HIV sufferers.  
 

PI: Xianjin Zhou; Co-I: Susan Powell, Vickie Risbrough

Peripheral circulating antibodies are largely blocked from entering brain parenchyma by blood brain barriers (BBB). However, ~0.1-0.2% of blood circulating antibodies can cross the BBB into brain tissue in healthy rodents and humans regardless of antibody specificities. High titers of autoantibodies against the synaptic protein NMDAR1 have been demonstrated to cause anti-NMDAR1 encephalitis producing psychosis, fear, anxiety, and many other psychiatric symptoms in addition to neurological symptoms. On the other hand, low titers of anti-NMDAR1 autoantibodies are common and present in ~10% of schizophrenia and other psychiatric disorders as well as ~5-10% of the general human population. However, the long-term effects of low titers of anti-NMDAR1 autoantibodies on human mental health are unknown. 
We are interested in understanding the potential role of synaptic autoimmunity, particularly anti-NMDAR1 autoimmunity, in the pathogenesis of psychiatric disorders.  We have developed modeling mice carrying low titers of anti-NMDAR1 autoantibodies against specific NMDAR1 antigenic epitopes to address the following questions:

1. Whether and how neuroinflammation facilitates generation of synaptic autoimmunity, particularly anti-NMDAR autoimmunity
2. Whether and how anti-NMDAR1 autoantibodies against different NMDAR1 antigenic epitopes may alter NMDAR functions differently and thereby cause different biological and behavioral phenotypes related to a variety of human psychiatric disorders
3. Whether and how different brain regions may have different vulnerabilities to the chronic effects of low titers of anti-NMDAR1 autoantibodies
4. Whether and how the MHC locus is involved in the generation of synaptic autoimmunity.