Neural Models of Normal and Abnormal Behavior: What Do Schizophrenia, Parkinsonism, Attention Deficit Disorder, and Depression Have in Common?

Defense Advanced Research Projects Agency and Office of Naval Research (N00014-95-1-0409); National Science Foundation (IRI-97-20333

Assessing mechanisms driving increased nicotine use in schizophrenia using the MAM rodent model

Rates of smoking are 2-3 times higher among individuals with schizophrenia relative to the general population, posing a significant exacerbation of health and socioeconomic disparities. While the cause of this elevation is unknown, two prevalent hypotheses are that nicotine, the primary reinforcing component in cigarettes, is particularly rewarding to individuals with schizophrenia, or that these smokers smoke in an attempt to “self-medicate” their symptoms. The present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia to evaluate these hypotheses. In order to explore the “reinforcement hypothesis”, MAM and control (CTL) animals were allowed to self-administer nicotine across a range of doses and responding and intake of nicotine were compared. The “self-medication” hypothesis was evaluated by examining the effects of acute and chronic nicotine on several established behavioral paradigms known to be disrupted in the MAM model. Additionally, the effects of acute and chronic nicotine on neurophysiological dysfunction, including elevated VTA dopamine population activity and elevated ventral hippocampal (vHipp) activity, were observed. Our findings demonstrated that self-administration of nicotine, alone or in combination with another reinforcer, was not increased in MAM rats, suggesting that schizophrenia pathophysiology modeled by MAM does not confer increased nicotine reinforcement. Conversely, we observed nicotine-induced improvements in prepulse inhibition of startle and novel object recognition among MAM rats, as well as a normalization of elevated VTA dopamine and vHipp neuronal activity in these animals. Together, these findings lend greater support for a “self-medication” hypothesis behind increased smoking in schizophrenia and illustrate the potential utility of nicotinic modulation in future pharmacotherapies for certain schizophrenia symptoms

Neural Dynamics Underlying Impaired Autonomic and Conditioned Responses Following Amygdala and Orbitofrontal Lesions

A neural model is presented that explains how outcome-specific learning modulates affect, decision-making and Pavlovian conditioned approach responses. The model addresses how brain regions responsible for affective learning and habit learning interact, and answers a central question: What are the relative contributions of the amygdala and orbitofrontal cortex to emotion and behavior? In the model, the amygdala calculates outcome value while the orbitofrontal cortex influences attention and conditioned responding by assigning value information to stimuli. Model simulations replicate autonomic, electrophysiological, and behavioral data associated with three tasks commonly used to assay these phenomena: Food consumption, Pavlovian conditioning, and visual discrimination. Interactions of the basal ganglia and amygdala with sensory and orbitofrontal cortices enable the model to replicate the complex pattern of spared and impaired behavioral and emotional capacities seen following lesions of the amygdala and orbitofrontal cortex.National Science Foundation (SBE-0354378; IIS-97-20333); Office of Naval Research (N00014-01-1-0624); Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-95-1-0409); National Institutes of Health (R29-DC02952

Genetic and Environmental Interactions on Schizophrenia-Like Phenotypes in CHL1 Deficient Mice

Schizophrenia is a debilitating disorder which is often characterized by dysregulation of the processing of sensory information. Schizophrenia has been shown to have a strong genetic component, as well as a strong environmental component. As such, a number of hypotheses such as the diathesis stress hypothesis have been developed to explain the etiology of schizophrenia. As most of these theories attempt to account for a genetic and an environmental factor, they are often viewed as double-hit models of schizophrenia. Several theories have emerged as potential explanations for the symptoms of schizophrenia. The dopamine hypothesis suggests that the basal level of dopamine transmission within the mesolimbic and mesocortical pathways is increased in schizophrenia. The glutamate hypothesis suggests that increased glutamate transmission in the striatum combined with NMDA receptor hypofunction could result in some of the symptoms of schizophrenia. Both the dopamine and the glutamate hypothesis draw on the idea that individuals with schizophrenia show heightened neural activation as compared with non-schizophrenics. The developmental theory of schizophrenia posits that insults to the brain occurring during development may causes changes in the brain which result in the symptoms of schizophrenia later in life. In this study, CHL1 deficient mice, an animal model of schizophrenia were compared with their wild type littermates on measures of neuronal activation and latent inhibition, a measure of normal attentional and sensory processing. Additionally, some mice from both genotypes were selected to receive stress. It was found that all unstressed mice as well as the wild type stressed mice showed latent inhibition. The stressed CHL1 deficient mice did not show latent inhibition, the absence of which is associated with the positive symptoms of schizophrenia. These results provide support for a double hit (environment x genetic) account of schizophrenia

Modeling HIV-1-Associated Neurocognitive Disorders and the Therapeutic Effects of the Phytoestrogen Metabolite S-Equol in the HIV-1 Transgenic Rat

HIV-1 associated neurocognitive disorders (HAND) continue to afflict individuals with HIV-1 in the combination antiretroviral treatment (cART) era, most notably affecting executive function, as well as preattentive processing. Currently, there is no effective treatment for HAND, with only adjunctive treatment targeting symptomatic relief. There were two hypotheses in this dissertation: 1) that HIV-1 Tg rats will show disruptions in measures of executive function and preattentive processing, as well as neural network alterations in the prefrontal cortex (PFC), a brain region implicated in executive function, and 2) that administration of the phytoestrogen metabolite S-equol will improve performance as measured by executive function and attention, as well as neuronal network complexity in the PFC. In experiment 1, using prepulse inhibition of the auditory startle response and a series of operant tasks, deficits were revealed in perceptual sharpening, sustained attention, and core components of executive function. Daily oral S-equol treatments (0, 0.05, 0.1, and 0.2 mg), administered to the animals at 6-8 months of age, improved the performance of the HIV-1 Tg animals on the sustained attention task. Assessment of neuronal networks with diOlistic labeling of pyramidal neurons in the PFC suggested that the 0.2 mg dose of S-equol ameliorated alterations in the HIV-1 Tg animals as well. In experiment 2, treatment with S-equol (0.2 mg), begun at 2-3 months of age, significantly delayed or prevented deficits in sustained attention. HIV-1 Tg animals that received S-equol also displayed enduring improvements in performance one month after the treatment ended, an effect not detected in any of the other groups. However, further assessments of increased demands on sustained attention as well as selective attention did not further differentiate the HIV-1 Tg and control animals. In summary, the HIV-1 Tg rats displayed impaired performance in preattentive processing, attention, and executive function, prior to any clinical signs of wasting. S-equol was effective in both ameliorating and preventing attentional deficits, suggesting its potential use as a therapeutic for neurocognitive impairments in HAND

LATERAL HABENULA AND ENDOCANNABINOID REGULATION OF STRESS-RELATED BEHAVIOR

Major depressive disorder (MDD) affects over 300 million people and is the largest contributor to disability worldwide. Strategies used to cope with stress impact the onset and maintenance of MDD and other stress-related disorders. Clinical and preclinical data indicate that individuals with stress-related disorders and rodents exposed to chronic stress exhibit impaired flexible decision-making and coping behaviors. The lateral habenula (LHb) is a key brain region that contributes to stress and cognitive performance via indirect projections that effectively inhibit the activity of downstream monoaminergic nuclei orchestrating behavioral responses to stress. We have shown that endocannabinoid (ECB) signaling is recruited in the LHb during stress. However, ECB contribution to stress-induced alterations in LHb activity, the impact of chronic stress on LHb recruitment during task performance, and whether the ECB system can be targeted to reverse the effects of stress remain largely unknown.This dissertation details my investigation of the impact of stress on the ECB system within the LHb and its contribution to stress-induced behavior. I addressed these questions using fiber photometry, site-specific pharmacology, deep learning behavioral classifiers, and ex vivo patch clamp electrophysiology, I found that chronic stress did not disrupt operant-based behavioral flexibility but did alter LHb calcium dynamics in a sex- and stress-dependent manner, which may underlie increased task engagement. Additionally, augmentation of the cannabinoid type 1 receptor signaling within the LHb did not disrupt flexible decision-making. When I site-specifically augmented the ECB 2-arachidonoylglycerol within the LHb under conditions of acute or chronic stress, I found that it did not affect coping behavior but did reduce the activation of the medial ventral tegmental area, a major downstream dopaminergic center. Lastly, I assessed ECB regulation of inhibitory inputs to LHb neurons that project to the rostromedial tegmental nucleus (LHbRMTg) in stress-naïve and chronically stressed rats. I found that chronic stress exposure recruits ECB tone in the LHb to reduce inhibitory events in LHbRMTg neurons. However, I did not observe an effect of CUS exposure on baseline inhibitory transmission. My dissertation provides insight into the interaction between stress and ECBs to shape LHb involvement in flexible decision-making, stress coping behavior, and circuit-dependent LHb activity. My results underscore the complex nature of LHb contributions to goal-directed behavior

A Repeated Amphetamine Model of Impaired Attention in Schizophrenia.

Cognitive impairments, including deficits in attention processing, represent major and central elements of schizophrenic symptoms. First- and second-generation antipsychotic drugs can effectively mitigate the florid symptoms of psychosis. However, treating schizophrenia’s cognitive deficits remains problematic and has met with limited success. Evidence indicates that the basal forebrain cholinergic system (BFCS) is an essential component of the neuronal circuitry involved in mediating attention processing - an important aspect of cognition. This thesis is based on the core hypothesis that cholinergic dysregulation contributes to the cognitive impairments associated with schizophrenia. Using a repeated-amphetamine (AMPH) rat model of schizophrenia, the following main hypotheses are tested: 1) Repeated, escalating AMPH administration, followed by ‘AMPH-challenges’ at previously innocuous doses, results in performance impairments on a task that measures sustained attention. 2) The consequences of repeated-AMPH administration and subsequent challenge dosing in task-performing animals include dysregulated cortical cholinergic transmission. 3) In AMPH-pretreated animals performing a sustained attention task; sub-chronic, low-dose administration of antipsychotic drugs will attenuate performance impairments. The present findings provide evidence for aberrant regulation of the BFCS and impaired sustained attention processing in a repeated-AMPH model of schizophrenia. Specifically, pretreatment with AMPH resulted in attenuated performance associated cortical cholinergic transmission. This effect was evident only under conditions of task performance, and was not apparent in passive, non-performing animals. Cholinergic abnormalities were found to actually precede task onset, indicating that they contributed to rather than resulted from impaired performance. Furthermore, low doses of commonly prescribed first- and second-generation antipsychotic drugs were found to attenuate these attentional impairments, although the effects on cortical cholinergic transmission in task-performing animals remain speculative. Theses data are consistent with the hypothesis that the basal forebrain cholinergic system represents a principle component in the neuronal dysregulation mediating schizophrenia’s cognitive impairments. Expanding this hypothesis, these data elucidate the dynamic nature of this dysregulation in response to different stimulus environments. Collectively, these experiments demonstrate the potential usefulness of this procedure for modeling aspects of impaired cognition in schizophrenia and may serve as a starting point for pre-clinical efforts aimed at discovering and developing novel, pro-cognitive drugs to improve the cognitive deficits of schizophrenia.Ph.D.PsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/58517/1/vinmarti_1.pd

Involvement of dopamine in the nucleus accumbens and prefrontal cortex in cocaine-associative learning

textStimuli formerly associated with cocaine-taking behavior are known to elicit physiological changes and craving in cocaine-dependent individuals. This is a result of learned associations between an environmental stimulus and the effects of cocaine, and is believed to be a major factor that leads to relapse in recovering cocaine addicts. A precise neural mechanism underlying how cocaine-paired stimuli produce craving and drug-taking behavior is currently unknown. Synaptic plasticity is known as a neural basis for associative learning. A modulatory role of a neurotransmitter, dopamine (DA), in synaptic plasticity has been implicated. Moreover, recent studies indicate that DA is particularly important during acquisition of associative learning, but less important as learning progresses. Yet, this notion has not been fully investigated using cocaine as a reinforcer. The nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) brain regions, are both largely implicated in drug addiction. Using an animal model of drug- taking behavior in conjunction with an in vivo microdialysis technique, the dissertation experiments determined the involvement of DA in during distinctive stages of cocaine associative learning. Results from the experiments showed that NAcc DA was responsive to cocaine-paired stimuli during early, but not the late stages of cocaine associative learning while responsiveness of mPFC DA to cocaine-paired stimuli was enhanced with extended conditioning experience. The results indicate that brain areas responsive to conditioned stimuli transfers as associative learning progresses. These findings suggest that a dynamic role of DA in distinctive brain regions should be taken into account during treatment and relapse prevention of cocaine addiction.Pharmac

Mesolimbic Dopamine Involvement in Pavlovian and Operant Approach Behaviors

Thesis advisor: Jon C. HorvitzPrevious research has yielded conflicting results regarding the involvement of mesolimbic dopamine in Pavlovian and operant tasks. While there is abundant evidence that an operant lever press requires intact dopamine (DA) D1 transmission in the nucleus accumbens (ACB) and in the basolateral amygdala (BLA), there is conflicting evidence regarding the specific brain sites at which DA mediates a Pavlovian approach response. The present study was designed to compare the effects of ACB and BLA D1 receptor-blockade on an operant and Pavlovian task, while minimizing differences in behavioral response topography. Animals were trained on either a Pavlovian cued approach task or an operant cued nosepoke task. In the Pavlovian approach task, a tone signaled a pellet delivery to which animals responded with a head entry into a food compartment. In the operant nosepoke task, animals were trained to emit a nosepoke in response to the same tone, in order to trigger a pellet delivery. Bilateral microinfusions of the D1 antagonist SCH 23390 (0, 1 or 2 microgram/side) into either the ACB or the BLA produced a dose-dependent disruption of the operant nosepoke. In contrast, the Pavlovian cued approach response was unaffected by D1 antagonist microinfusions into either the ACB or the BLA. In addition, infusion of SCH 23390 into either site suppressed general locomotion. The results suggest a dissociation of the anatomical substrates mediating an operant nosepoke and a Pavlovian approach, despite similar response topographies. These findings are consistent with the notion that D1 activity at the ACB and BLA plays a role in the expression of operant responses, but not in the expression of Pavlovian approach responses.Thesis (PhD) — Boston College, 2010.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Psychology