Kyle S. Smith - US grants

DESCRIPTION (provided by applicant): Mounting evidence indicates that procedural learning and habit formation require a restructuring of neural activity patterns in anatomical loops connecting the cortex with the striatum of the basal ganglia. Yet remarkably little is known about where and how these critical activity changes take place. This is a pressing issue for modern research and the broad goal of my proposed work. Technological advancements have now made it possible to record or silence the activity of large populations of neurons in spatially segregated brain areas at the same time. Harnessing these new tools, I will first simultaneously evaluate neural activity in cortex sites (infralimbic and premotor) and striatum sites (dorsolateral striatum) identified in brain lesion studies as critical nodes in the larger brain network for habit formation as rats are extensively trained on a maze task. This will allow me, for the first time, to track the restructuring of neural activity that encodes procedural learning and habits in both cortex and striatum, as well as evaluate the flow of information within corticostriatal loops as learning progresses. I will subsequently incorporate new gene-based methods to silence the activity of one habit site (in the infralimbic cortex), a procedure that is known to block habit-based behaviors, while simultaneously recording from neurons in another (in the dorsolateral striatum). In this way, I can evaluate how neural activity patterns that emerge with habit formation become delayed or obstructed when vital pathways of the cortex- basal ganglia are 'short circuited'. Finally, throughout the proposed I will incorporate anatomical tracing techniques to identify crucial circuit connections for learning-related plasticity within these sites, and will also include tests of behavioral sensitivity to reward value at different learning stages to evaluate the transition of behavior from 'goal-directed'or 'habitual'as formally defined. This research will use state-of-the art genetic and physiology techniques to identify the critical patterns of activity that emerge in the cortex and basal ganglia when a skill is learned and becomes a habit with practice. Understanding the brain basis of normal habit learning will be key to understanding how abnormalites of brain activity contribute to behavioral disabilities (e.g. in Parkinson's and Huntington's Disease) and compulsions (e.g., in drug addiction and obsessive-compulsive spectrum disorders).

Habits are a part of all animal life. Despite their ubiquity, it remains poorly understood how habits are formed and maintained in the brain. This research project will study how habits are represented in brain activity and how changing that activity can change habits. Science generally lacks an understanding of how fluctuating patterns of brain activity control behaviors like habits because, until recently, tools were not available to manipulate those brain patterns. Using cutting-edge techniques to do so, this work tests a central hypothesis that habits are controlled by the timing of brain activity related to when a habit is initiated and executed. Specifically, prior studies have uncovered a burst of brain activity as a behavior starts that correlates with how habitual the behavior is. This research evaluates how this pattern arises in the brain and whether it controls how habitual a behavior is by using tools to both monitor and manipulate the brain at the sub-second time-scale. Results will provide a rich understanding of how habits arise out of precisely timed bursts of brain activity. As part of this project, the cutting-edge research techniques are taught to undergraduate neuroscience students, which is a vital but lacking ingredient in their education. These techniques, and the brain basis of habits in general, also are taught to grade-schools and the public through outreach activities to convey progress science is making on understanding habits. Underrepresented individuals participate in all aspects of the research and outreach.

In the brain, the dorsolateral striatum (DLS) and its dopamine input from the substantia nigra have long been implicated in habits. Neural recording studies have uncovered an activity pattern in these areas that characterizes habits, which involves a spiking burst at the start of behavior and diminished spiking mid-behavior. These dynamics suggest that it is the timing of brain activity that helps dictate whether or not a learned behavior occurs habitually. To test this, rats are exposed to lever-pressing and maze-running tasks that provide a screen of behavioral measures for habits. Activity in the DLS is recorded using electrodes as animals form habits and then modify them. Using optogenetics, in which DLS activity can be manipulated using pulses of light, the strength of the DLS activity is manipulated and consequences on habitual behavior and ongoing DLS dynamics assessed. The first and second objectives are to test if the strength of DLS activity at the start of a behavior is sufficient and necessary for that behavior to be expressed as a habit and for habit-related DLS activity to be maintained over time. The third objective is to test if start-related activity of dopamine input to the DLS is also critical for habits and for the start-related DLS activity that represents habits. Collectively, this work answers a long-standing question of how step-to-step fluctuations in DLS activity guide a behavior towards habitual expression and will merge isolated behavioral and neuroscience approaches to do so.

Drug addiction involves an excessive motivation to pursue and consume drugs. Part of this motivation is thought to involve the attribution of value to drug-paired cues. Cues for rewards, including drugs and food, can become motivational targets and attract attention and behavior. In the brain, a basic sketch of areas responsible for this process is known and includes the nucleus accumbens (NAc) and ventral pallidum (VP). Although these areas are bidirectionally connected as a circuit, little is known about how motivation arises out of their circuit dynamics. To address this, the proposed research will incorporate a method called chemogenetics for relatively non-invasive ?remote control? perturbation of brain activity. Combining this method with transgenic delivery strategies, we will both increase and decrease activity in pathways connecting the NAc and VP to evaluate their role in the motivational attraction to reward cues. This motivational process is exemplified by sign-tracking behavior, in which animals appetitively engage with a cue predicting reward. In the proposed research, connections between the NAc and VP will be manipulated using DREADDs to assess the role of these pathways in acquiring and expressing the sign-tracking behavior. Recordings of neural activity and gene expression assays will complement these experiments in order to establish neural activation patterns that change in register with changes in motivated behavior. We will similarly test the role of neurons in the VP expressing acetylcholine, which receive NAc input and are hypothesized to guide attention towards reward cues. Results showing how NA-VP circuits control motivation, and what neural activity signatures map on to increases and decreases in motivation, will provide critical reference points for an understanding of how pathway-specific changes in brain activity could contribute to excessive motivation in addictive behaviors. The relative non-invasiveness of the procedure also carries translational potential for disrupting severely excessive reactions to drug-associated stimuli.

Project Summary Individuals with fear disorders such as post-traumatic stress disorder (PTSD) experience excessively strong and intrusive fear memories about stimuli that were encountered during a prior trauma, including individual sounds or visual stimuli (?cue-specific? fear memory) or the combination of stimuli that together define the place in which the event occurred (?contextual? fear memory). The memories may have been formed recently or long ago (?remote? memories), in which case they may plague a person for a substantial portion of his/her life. The development of effective therapies depends on a thorough understanding the neural mechanisms that underlie these different types of fear memories, as well as fear extinction, which is the basis for exposure- based therapy commonly used to reduce fear in humans. To date, a substantial body of research has identified discrete neural systems that support recent versus remote contextual memory, and other studies have identified the substrates of recently-acquired cue-specific memory and extinction, but very little work has focused on the brain mechanisms involved in remote cue- specific memory and extinction. This is important to resolve particularly with respect to PTSD since individuals often do not seek therapy until long after the traumatic event, especially in cases of combat trauma or sexual assault. To address this, the proposed research advances a new theoretical model of the neural circuits that underlie remote cue-specific fear memory and extinction. This model is based on new data from our laboratory and combines state-of-the art chemogenetic and optogentic-anatomical approaches to test the hypotheses that a) communication between the retrosplenial cortex and secondary sensory cortices is necessary for remote cue-specific fear memory, and b) the postrhinal cortex mediates the context-dependency of extinction of remote cue-specific fear.