Bo Li, Ph. D. - US grants

DESCRIPTION (provided by applicant): The synaptic circuitry of the lateral habenula and behavioral depression. The neural basis of mood disorders is poorly understood. As a consequence, efforts to develop more effective therapies for depression have largely been unsuccessful. Recent studies indicate that neurons in the lateral habenula (LHb) signal disappointment and may play an important role in depression, however the mechanisms by which the LHb contributes to depression are unknown. Here, we will test the central hypothesis that aberrant activity in the synaptic circuitry of the LHb underlies behavioral depression, and that normalization of LHb neuronal activity is integral to the efficacy of anti-depression treatments. The overall goal of this research program is to gain a better understanding of the cellular changes responsible for the pathogenesis of depression. Using animal models of depression, aberrant neuronal activity in the LHb will be assessed and its underlying synaptic mechanisms will be determined. Furthermore, by selectively manipulating the activity of LHb neurons and determining the behavioral outcomes, the causal relationship between aberrant LHb neuronal activity and behavioral depression will be tested. Importantly, this research program will result in the development of methods that allow the modulation of depression-like behavior in animals. A number of complementary methodologies will be used, including behavioral assays, electrophysiology, two-photon imaging, in vivo circuit tracing, electrical deep brain stimulation, molecular genetics, and optogenetic techniques. The SPECIFIC AIMS are: SA1: To define the synaptic circuitry of hyperactive LHb neurons in animal models of depression. SA2: To determine the synaptic mechanisms underlying aberrant LHb neuronal activity in animal models of depression. SA3: To manipulate the synaptic circuitry of the LHb in order to modulate behavioral depression.) Developing more effective treatments for depression is an important goal. Current antidepressants suffer from critical limitations due to a lack of understanding of the pathophysiology of depression. Results from the proposed research will provide important insights into the cellular and circuit mechanisms of depression that may lead to novel and effective treatments capable of ameliorating some forms of depressive disorders.

DESCRIPTION (provided by applicant): The amygdala is critical for fear processing and fear regulation. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear learning. In particular, neurons in the lateral subdivision of the CeA (CeL), which tonically inhibits the medial subdivision of CeA (CeM) and thereby gates fear expression, are thought to encode learned fear. However, the mechanisms by which CeL contributes to fear learning remain unknown. In addition, the link between the role of CeL in fear learning and its known role in fear expression is also unclear. The objective of the proposed project is to elucidate the mechanisms by which the central amygdala contributes to fear learning and orchestrates fear expression in Pavlovian fear conditioning. We will focus on distinct classes of inhibitory neurons in the CeL. Our central hypothesis is that fear conditioning induces cell type-specific synaptic modifications in CeL circuits that serve as fear memory traces. We further propose that these memory traces act to promote the inhibition of CeL output during fear memory recall, thereby disinhibiting CeM and releasing fear expression. We designed an integrated approach, combining molecular genetic tools, in vitro and in vivo electrophysiology, and optogenetic and chemical-genetic techniques, to test our hypotheses in the following Specific Aims: 1) to delineate the functional organization of the CeA inhibitory circuits; 2) to determine the mechanisms of the fear conditioning-induced synaptic plasticity in CeL; and 3) to determine the role of specific CeL inhibitory circuits in fear conditioning. Findings from this project will have important clinical implications, as dysfunction of fear regulation mechanisms is implicated in a number of psychiatric conditions, including generalized anxiety disorder and post-traumatic stress disorder.

? DESCRIPTION (provided by applicant): The basal ganglia-habenula circuitry in reward processing the overall goal of this project is to investigate the basic brain mechanisms underlying reward processing. Recent studies demonstrate that the lateral habenula (LHb) provides valence signals to the midbrain dopamine areas. However, in part owing to the challenges in monitoring and manipulating activities in the LHb circuitry, the roles of this circuiry in more complex behaviors still remain elusive. In particular, how LHb neurons acquire the valence signals, and whether and how these signals are used to guide behavior, are questions that remain unresolved. Bridging these gaps is of great clinical significance, because LHb dysfunction is implicated in the pathogenesis of depression, a major psychiatric disorder in which deficit in reward processing is the hallmark. In the proposed study, we plan to approach these questions by investigating how functionally distinct groups of neurons in the basal ganglia-lateral habenula circuitry coordinate and participate in reward processing, thereby influencing behavior. For this purpose we have devised an integrated strategy that combines molecular genetic tools together with electrophysiological, imaging, optogenetic, chemogenetic, and behavioral techniques. Findings from this research program will provide novel insight into the synaptic, cellular, and circuit mechanisms by which the basal ganglia-lateral habenula circuitry contributes to reward-related processes.

Dysfunction of distinct amygdala circuits in a 16p11.2 model of autism The overall goal of this project is to investigate the brain mechanisms underlying the abnormal repetitive behaviors and emotional processing in a genetic model of autism spectrum disorders (ASD), which was developed in mice to mimic a microdeletion on human chromosome 16p11.2, one of the most common genetic variations found in ASD. Besides other symptoms, patients with this deletion show severe repetitive behaviors and anxiety, two frequently comorbid symptoms in ASD. Despite intensive study, the mechanisms underlying the repetitive behaviors in ASD and the high prevalence of comorbidity between ASD and anxiety disorders remain largely unknown. In the proposed study, we plan to approach these questions by investigating the role of distinct amygdala circuits in abnormal habitual behaviors and fear processing in mice heterozygous for a deficiency allele of the region corresponding to the human 16p11.2, named as the 16p11.2 df/+ mice. We will test the hypothesis that dysfunction of distinct amygdala circuits in the 16p11.2 df/+ mice causes abnormal habitual behaviors and impairment in fear processing characteristic of ASD. In order to test this hypothesis, we have devised an integrated strategy that combines molecular genetic tools together with electrophysiological, chemogenetic, and behavioral techniques. Findings from this research program will provide novel insight into the synaptic, cellular, and circuit mechanisms by which dysfunction of distinct amygdala circuits contributes to abnormal behaviors related to ASD.

The central amygdala circuits in motivated behaviors Project Summary The central amygdala (CeA) contains heterogeneous cell types, with somatostatin-expressing (SOM+) neurons and protein kinase C-?-expressing (PKC-?+) neurons being two largest and largely non-overlapping populations. Previous studies have mainly focused on the roles of these neurons in fear conditioning, revealing that SOM+ and PKC-?+ CeA neurons differentially contribute to fear learning and expression. However, it is long recognized that the CeA contributes not only to behaviors driven by aversive stimuli, but also to those driven by appetitive stimuli, and to the generation of anxiety state. Indeed, recent studies show that distinct types of CeA neurons, such as SOM+ neurons, can drive appetitive behaviors and heightened anxiety. However, how the SOM+ as well as PKC-?+ CeA neurons participate in divergent motivational behaviors remains poorly understood. Bridging this knowledge gap will have important clinical implications for improved treatments, as CeA dysfunctions have been implicated in mood- or motivation-related disorders, including anxiety disorders, depression and drug addiction. We will address this question by investigating the in vivo response properties of SOM+ neurons and PKC-?+ neurons in the CeA during behaviors driven by either reward or punishment, and determining how these responses are used to control the functions of downstream circuits and, hence, behavior. Our central hypothesis is that CeA neurons influence learning or expression of reward seeking and punishment avoidance through their long-range projections to different targets. Based on our preliminary results, we devised an integrated approach, combining in vivo imaging, fiber photometry, optogenetics, chemogenetics and novel behavioral techniques, to test our hypotheses in the following Specific Aims: Aim 1. To determine the roles of SOM+ CeA neurons in motivational behaviors. Aim 2. To determine the roles of PKC-?+ CeA neurons in motivational behaviors. Aim 3. To determine how a CeA-BNST circuit contributes to anxiety-related behaviors.

The overall goal of this project is to develop a reinforcement learning (RL) theory of motivation, understood here as motivational salience, and to test the conclusions of this theory using experimental observations obtained in the ventral pallidum (VP). Animals' actions depend on the shifting values of internal demands determined by physiological or behavioral conditions, such as thirst, hunger, addiction, specific nutrient deficiency, etc. These need-based modulations of the perceived values of reinforcements (reward or punishment} are described by a mathematical variable called motivational salience or, simply, motivation. Including motivation adds a new level of complexity to RL theory, and allows it to generate flexible ongoing behaviors. Here, we will investigate how motivation can be learned by neuronal networks to generate complex adaptive behaviors and compare the conclusions of our theory with the VP circuits. Previous studies indicate that the VP plays an important role in a variety of behaviors, potentially, by influencing motivational salience. In vivo recordings suggest that VP neuron firing correlates with motivational states. Lesions, pharmacological and optogenetic manipulations in VP cause profound changes in behaviors motivated by natural rewards or drugs of addiction. Dysfunction of this structure is linked to depression and drug addiction in humans. Our theoretical results suggest that distinct classes of neurons in the VP should play essential roles in representing either positive or negative motivational states. We further hypothesize that the functional interactions locally within the VP are critical for generating such signals that guide motivated behaviors. Consistent with predictions of RL theory, in our preliminary studies, we found that individual VP neurons could be classified as either positive or negative 'motivation neurons', as the activities of these neurons represented both expected values of outcomes and motivational states. When population activity is considered, representations of outcome expectation can be distinguished from representations of motivation fluctuating according to the animals' physiological states. Based on the preliminary data, we devised an integrated approach, combining studies in computational analysis and theory (Koulakov lab) with advanced molecular genetic tools, optogenetics, chemogenetics, electrophysiology, and imaging in behaving mice (Li lab), to test our hypotheses through the following Aims: Aim 1. To develop methods for identifying motivation in the population activity of VP neurons. Here we will use novel behavioral and computational methods to disambiguate representations of motivation and outcome expectation in neuronal responses. Aim 2. To develop reinforcement learning theory of motivation and to test its predictions using responses of VP neurons. Here we will develop the Q-learning theory of motivation and compare networks trained using this theory to responses of VP neurons. Aim 3. To identify the circuit basis of representations of motivation in VP neuronal populations. We will identify the network structure in Q-learning networks with motivation, and test predictions using opto- and chemogenetic manipulations in VP. RELEVANCE (See instructions): The neural mechanisms of motivated behaviors remain unclear. In the proposed research program, we will determine the precise circuit mechanisms and computations by which neurons in the ventral pallidum participate in modulating motivated behaviors. Findings from this project will have important clinical implications, as impairments in motivational processes are core features of depression and drug addiction.