Annegret Lea Falkner - US grants

DESCRIPTION (provided by applicant): How does the brain filter distracting visual information? It is well known that salient visual stimuli can elicit transient saccadic or attentional capture. This phenomenon is ecologically useful if the goal is to rapidly orient to a potential predator in the periphery, but highly detrimental if it distracts from a different goal such as monitoring elusive prey. Therefore, neural mechanisms for filtering distracting, irrelevant visual information are crucial for preventing wasteful saccadic or attentional shifts. This filtering may emerge as a direct consequence of lateral suppressive interactions between competing neural representations of visual stimuli, though the details underlying these processes are not well understood. The lateral intraparietal area (LIP) of the monkey encodes the relative priority of spatial locations, and activity in this brain area can reliably predict the locus of attention or the target of an upcoming saccade. Within LIP's "salience map," spatial locations compete using their activity for attentional and saccadic priority. Previous studies have explored how "top-down" excitatory processes such as motivation or attention can enhance the activity associated with behaviorally relevant stimuli in LIP, thus increasing their relative priority on this map. However, preliminary evidence suggests that lateral suppressive interactions in LIP operate in tandem with these excitatory processes and may be crucial for filtering distracting information and resolving competition between stimuli, though this has not yet been explored. In this proposal, my goal is to systematically explore the role of lateral suppressive interactions in LIP in filtering distracting visual information, and determine how this is related to saccadic behavior in the awake behaving monkey. We will use a combination of psychophysics and physiological recordings in LIP to investigate the following 3 aims: 1) Characterize the spatiotemporal properties of lateral suppression in LIP and how they are modulated by expected reward 2) Determine how these processes are related to saccadic behavior, and 3) Explore the mechanism of distractor filtering by using paired electrode recordings to directly compare the responses of competing stimuli. This research will hopefully give us insight into the general neural mechanisms that underlie the processes of spatial attention and saccadic decision making. This proposal offers significant health benefits to parietal patients, who exhibit extreme deficits in perception and oculomotor behavior. The first two aims would directly characterize unexplored areas of normal functioning, and the third aim could potentially lead to the identification of cellular populations for future drug targeting.

Project Abstract Many diverse neural disorders, including bipolar disorder, schizophrenia, post traumatic stress disorder, and conduct disorder, as well as certain types of cortical trauma can result in increased aggression. These effects can be severely compounded when paired with substance abuse. These behavioral effects can take the form of increased ?proactive? aggression-seeking behavior, increased ?reactive? aggressive action, or both. Many of these effects are believed to result from ?top-down? disinhibition of aggression-relevant circuitry, though there is little direct circuit-level or physiological evidence to support this. The goal of this project is to understand and dissociate the precise circuit roles of sources local and long-range inhibition to a hypothalamic neural locus with a clearly identified role in both proactive and reactive aggression. This will potentially lead to a broad new understanding of how activity within these circuits is shaped and gated by inhibition, and how these processes may go awry during social dysfunction. Furthermore, it will provide a much needed circuit-level framework to understand how such diverse disorders can result in similar aggressive phenotypes and may suggests specific circuit components as potential therapeutic targets. While decades of research have implicated the hypothalamus in the generation of ?reactive? aggression, its role in aggression seeking or ?proactive? aggression has been previously unclear. The candidate?s recent work has characterized a new and surprising role for a hypothalamic subdomain, the ventromedial hypothalamus, ventrolateral area, VMHvl, in proactive aggression seeking in addition to its known role in attack. Neurons in this area are active during aggression seeking, and stimulation of this area promotes both aggression seeking and future attack. This area receives direct intra-hypothalamic inhibition as well as inhibition from a number of upstream structures in the amygdala and forebrain, whose roles during proactive and reactive aggression may be dissociable. Newly developed techniques for cell-type specific imaging of deep neural structures now, for the first time, allow interrogation of individual circuit components and can also be used to detect real-time changes in inhibition. This proposal leverages the power of mouse genetics in tandem with new strategies for optical recording, chloride FRET sensing, and cell type specific functional manipulation (Aim 1) to elucidate the roles of VMHvl excitatory and inhibitory subpopulations during aggression seeking and aggression action. In the independent phase of this project, the candidate will expand the scope to map the regulatory roles of sources of long-range inhibition onto the VMHvl and model their effects on the output of aggression- relevant neurons (Aim 2). This will provide a full model how individual neurons become selective for social seeking or action and will also point to neural pathways that could be potential points of intervention during social dysfunction. While this project is focused on aggression-seeking behavior in male mice, these tools can be broadly harnessed for future research on other social seeking behaviors in both females and males. This project brings together an experienced group of mentors and collaborators who will provide critical training for the candidate?s short-term and long-term success, including expertise in genetic targeting strategies, optical recording, functional manipulation, and in vivo ?optrode? recording. The proposed training program combines technical training and formal mentorship alongside the development of professional skills. The goals outlined in this proposal build upon the candidate?s background as primate physiologist and will equip the candidate to successfully transition to leading a laboratory focused on understanding the neural circuitry underlying social motivation.

Many diverse neural disorders as well as certain types of cortical trauma can result in increased aggression. These behavioral effects can take the form of increased proactive aggression-seeking behavior, increased reactive aggressive action, or both, suggesting that these behaviors may be independently regulated. While these effects are believed to result from ?top-down? disinhibition of aggression-relevant circuits, there is little direct circuit-level or physiological evidence to support this. Our recent work has shown that the ventrolateral hypothalamus, ventrolateral area (VMHvl) controls the expression of both reactive and proactive aggressive behaviors and may represent a common pathway for functional inhibitory control of aggression. During the K99 phase of this proposal, we identified how an undescribed source of local inhibition to the VMHvl selectively gates aggression-seeking behavior. In addition to this local inhibition, the VMHvl receives inhibition from a number of upstream structures in the hypothalamus, amygdala and forebrain. These inputs likely have dissociable roles in the regulation of reactive and proactive aggression and may represent multiple independent pathways to dysregulate the circuit. Newly developed techniques for cell-type specific imaging of deep neural structures now allow interrogation of individual circuit components and can also be used to detect real-time changes in inhibition. This proposal leverages recent advances in cell-type and pathway specific targeting in mice in tandem with new strategies for optical recording, chloride FRET sensing, and functional manipulation to describe brain-wide circuits for inhibitory control of aggression. In this proposal, we aim to 1) Characterize and map the regulatory roles of sources of long-range inhibition onto the VMHvl and model their effects on the output of excitatory aggression-relevant neurons, 2) Using a novel optical chloride sensor, explore whether activation of these upstream inhibitory control inputs results in functional inhibitory drive, and 3) Test whether upstream inputs for inhibitory control selectively target subsets of VMHvl neurons for proactive and reactive aggression. Together, these data will potentially lead to a broad new understanding of how activity within canonical circuits for aggression is shaped and gated by inhibition and how these processes may go awry during social dysfunction.

Project Summary Major depressive disorder (MDD) and associated anxiety disorders are the most prevalent and costly mental illnesses in the United States, with health spending on treatment recently exceeding $71 billion per year. It is now well established that MDD represents a spectrum of disorders, but current drug based approaches to treatment are temporally nonselective, and their efficacy varies highly across individuals. In this proposal, we explore a ?novel individualized intervention strategy,? wherein we aim to prevent and reverse MDD through closed-loop behavioral and neural circuit ?tuning?. While some individuals develop MDD as a result of a stressful life event, other individuals appear more resilient to stress-induced depression. Our goal in this proposal is to leverage recent advances in machine learning to identify and detect specific pro-resilient behaviors and patterns of activation in resilient individuals, and then use these data to ?steer? susceptible individuals into pro-resilient states. We will accomplish this in two phases. In the first phase, we will test whether modification of behavior alone can generate a pro-resilient state. We will take a novel quantitative approach to behavior analysis, using machine learning to identify specific micro behaviors that are unique to resilient individuals during a chronic social stress. Then, to test whether promoting these behaviors can provide depression-protective effects, we will then use a closed-loop strategy to detect ongoing behavior, and reinforce identified pro-resilient micro behaviors. Second, we will perform circuit-wide calcium recordings in the brain?s subcortical social behavior network and perform unsupervised detection of pro-resilience circuit motifs across the population. We will then use a novel closed-loop read-write strategy to optogentically ?tune? the circuit dynamics to mimic these pro-resilient states. We will further explore how these interventions can be accomplished at various time points relative to a stressful life event (before, during, and after) to test whether circuit intervention can potentially provide protective or restorative treatment. These data can potentially be used to develop novel behavior-based therapies for MDD, or to significantly refine the current use of deep-brain stimulation in order to generate pro-resilient states.

Abstract How does the brain generate and maintain a persistent high-aggression state? While pathological, persistent aggression is a common symptom in many diverse mental health disorders including schizophrenia, bipolar disorder, post-traumatic stress disorder, autism, Rett syndrome, and traumatic brain injury, we lack a fundamental understanding of the neural mechanisms underlying persistent social states. Many models of aggression posit that this dysregulation occurs through the failure of ?top-down? inhibitory control of subcortical circuits for aggression, through the circuit and synaptic basis for these models remain unclear. Here, we propose that pathological aggression may hijack circuit mechanisms used to generate persistent aggressive states in adaptive contexts. In particular, the experience of aggression has long been known to facilitate the emergence of a persistent high-aggression state, enabling animals to defend territory and status across long periods of time. Examining how experience ?updates? neural circuits in the healthy brain to facilitate future aggression provides a unique window on how these circuits become dysregulated under pathological conditions. What are the neural mechanisms underlying experience-dependent updating? To explore this, we will look longitudinally at the changing relationship between neural activity in the ventromedial hypothalamus, ventrolateral area (VMHvl), an aggression output area with a well-described role in aggression in both sexes, and its ?upstream? inhibitory inputs. In this proposal, we will test the novel hypothesis that aggression experience stabilizes a persistent aggressive state through a circuit ?rerouting? mechanism rather than changes in the activity of inhibitory control loci. Using a variety of methods for supervised and unsupervised behavioral analysis, virally mediated anatomical tracing, synaptic physiology, optogenetics and cellular resolution high-density recordings, we will look longitudinally at how experience alters the fundamental properties of this circuit to implement behavioral change. First, we will map the putative identity of circuit nodes with the architectural capacity to reroute inhibition and characterize the changes in synaptic strength of this circuit across experience. Next, we will specifically examine the relationship between the activity of the regulatory input and the circuit-level output across experience. Lastly, we will perform high-density population recordings to elucidate the changes in the underlying computations being performed by the circuit to stabilize a high aggression state. Together, these data will provide a comprehensive integrated framework for understanding how experience generates a persistent behavioral state, and will pave the way for novel activity-dependent tools that may be able to detect neural signatures of experience and behavioral persistence in patient populations at risk for aggression dysregulation.