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.

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.

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.