Sondra T. Bland - US grants

DESCRIPTION (provided by applicant): Project Title - Social Influences on drug reward and monoamines: Adolescent social deprivation, social clues, and sex differences. Early life adversity, including adverse events that occur during adolescence, can produce vulnerability to, or conversely, resistance to drug addiction. Factors that may influence whether these events produce vulnerability or resistance to addiction include those related to the individual, such as its gender;the drug class involved, such as opioids or psychostimulants;and the context in which drug taking occurs. In social species including rats, adolescent social deprivation (isolation rearing) has been used as a model of adolescent adversity that produces changes in social behavior as well as alterations in the responses to drugs of abuse. Isolation rearing can produce a reduction in the rewarding properties of drugs of abuse, thus causing resistance to the intrinsic reinforcement dimension of addiction. Increasingly, social cues during drug exposure are recognized as an important component of the context in which drug exposure takes place. Social interactions can be highly rewarding, especially during adolescence, and social cues can potentiate the rewarding effects of drugs. Isolation rearing can produce an increase in the importance of social interactions, thus causing vulnerability to the social context dimension of addiction. Thus, isolation rearing may produce both vulnerability and resistance to drug addiction via effects on two different dimensions of drug exposure. Here it is predicted that the influence of social context on the rewarding effects of drugs will depend on the social history (social deprivation or social experience) of the individual during the critical period of adolescence. Moreover, sex differences in the responses to both isolation rearing and drug exposure are known to occur so and these effects may differ between males and females. The proposed research addresses these issues by asking the following questions: Do social cues during exposure to the opioid oxycodone or the psychostimulant cocaine have a greater impact on drug seeking behavior in male and female rats that have been socially deprived during adolescence? Is the mechanism of these effects related to changes in the neurochemistry of neural circuits involved in reward? These questions will be addressed in two specific aims. Specific Aim 1 is to determine the effects of isolation or group rearing on social cue-induced changes in drug- seeking behavior in male and female rats using conditioned place preference. Specific Aim 2 is to determine the effects of social cues during drug exposure on extracellular dopamine and serotonin in the nucleus accumbens and medial prefrontal cortex of isolation- or group-reared male and female rats using in vivo microdialysis. Understanding how drug and social rewards interact and how this may be mediated by the prior social experience and the sex of the individual can contribute to the development of interventions specific to at- risk individuals. PUBLIC HEALTH RELEVANCE: This proposal explores the role of social deprivation during adolescence on the impact of social cues on the rewarding properties and neurochemistry-altering properties of drugs of abuse, and asks whether this depends on the sex of the subject. The results have the potential to provide evidence that early adversity can interact with the drug-taking environment to influence the vulnerability to addiction, and may contribute to the development of interventions specific to at-risk individuals.

DESCRIPTION (provided by applicant): The consequences of youth violence and aggression pose a significant public health problem, and the risk of later psychopathologies such as drug abuse, mood disorders, and abusive parenting is increased in individuals with a history of aggressive behavior during adolescence. However, much remains unknown about the neural substrates involved in aggression and its development. The work proposed here will use isolation rearing, an animal model of adolescent social adversity, to explore the role of the medial prefrontal cortex (mPFC) in aggression in male and female rats, focusing on glutamate and dopamine (DA) neurotransmission as potential mechanisms for the dysregulation of social behavior that occurs as a consequence of isolation rearing. Glutamate and DA modulate each other bidirectionally and are crucial for plasticity and proper mPFC function. The mPFC is critically important for executive function, including appropriate social behavior, and much of the development of the mPFC occurs during adolescence and into early adulthood. Although some of the effects of isolation rearing on social behavior have been shown to be reversible simply by rehousing isolates with a group, this is not likely to be a valid model of how socialization occurs in humans, as clinical evidence indicates that many aggressive adolescents become aggressive adults. Therefore we will assess the effects of single or repeated social experience after either isolation or group rearing of adolescent rats. The proposed work asks whether the activation of immediate early gene protein products (c-fos and Arc) and the plasticity-related protein PSD-95, all of which are sensitive to or involved in glutamate and DA signaling, are altered after isolatio rearing in response to subsequent social interaction with a novel same-sex rat, and whether changes in these proteins are related to the increase in aggression observed after isolation rearing. Alterations in postsynaptic interactions of DA and glutamate signaling and the role of PSD-95 in these interactions will be explored by assessing colocalization of DA D1 and glutamate NMDA receptors with PSD-95 using immunoflurorescence and confocal microscopy. Experiments will explore presynaptic changes produced by isolation rearing and subsequent social experience in the neurotransmitters glutamate and DA using in vivo microdialysis. In addition, mPFC microinjections of NMDA receptor (D-cycloserine) and DA D1 receptor (SKF 38393) agonists will be used to determine whether these neurotransmitter systems act in the mPFC to mediate the increased aggression observed in isolation reared rats. This will be done with 3 Specific Aims. Specific Aim 1 is to determine social-interaction induced changes in mPFC functional activation and plasticity after isolation rearing in male and female rats. Specific Aim is to determine the role of mPFC glutamate and NMDA receptors in aggressive behavior after isolation rearing in male and female rats. Specific Aim 3 is to determine the role of mPFC DA and DA D1 receptors in aggressive behavior after isolation rearing in male and female rats.

? DESCRIPTION (provided by applicant): Building Research Achievement in Neuroscience (BRAiN): Student Training through Institutional Partnerships will bridge the neuroscience research participation gap by preparing in the Rocky Mountain and Southwest Region undergraduates nationally underrepresented in biomedical and behavioral sciences for successful entry to neuroscience Ph.D. programs. BRAiN unites preexisting formal research and education programs at diverse institutions: the BRIDGE program to advance Native American students to Baccalaureate of Science degree programs in biomedical sciences program and the Biomedical Research Support (MBRS) Research Initiative for Scientific Enhancement (RISE) programs at New Mexico State University (NMSU); and the undergraduate Brain and Behavior program of the Department of Psychology at the University of Colorado Denver downtown campus (UCD). Importantly in BRAiN these undergraduate programs collaborate thoroughly with the Neuroscience Graduate Program at the University of Colorado Denver in the Anschutz Medical Campus (NSP at UCAMC), home to a T32 Neuroscience Training Grant. Broad participation in the Ph.D. neuroscience/behavior pipeline will be enabled through pursuit of three specific aims: (1) Recruitment of 55 BRAiN Scholars from diverse demographic groups that are nationally underrepresented in biomedical and behavioral neuroscience research; (2) Development of the Neuroscience/Behavior research expertise and professional skills of BRAiN Scholars; (3) Retention of BRAiN Scholars in Neuroscience/Behavior research through enrollment in postgraduate programs. In the past funding period BRAiN has attained solid achievement. BRAiN will provide intensive training that combines mentored independent research with student development of a rich knowledge base in neuroscience core concepts and computational neurobiology using MATLAB through summer courses at UCAMC. Emphasis will be placed on enhancement of mentorship skills through activities such as the Neuroscience Mentor Academy where faculty will meet to discuss student training, program evaluation, and curriculum reform. Taken together, proposed activities will provide an integrated research and professional development experience across multiple sites that leverages 21st century resources for scientific investigation and is responsive to practical aspects of contemporary student life.

Summary Social fear is a learned behavior and can be adaptive, but heightened social fear is frequently a component of anxiety-related disorders such as social anxiety disorder (SAD) or post-traumatic stress disorder (PTSD). Fear responses, both learned and innate, are made up of a continuum of adaptive behaviors and these defensive responses become maladaptive in anxiety disorders. We have developed a novel conditioned social fear paradigm in rats in which a footshock unconditioned stimulus (US) is paired with a social stimulus (a novel same-sex conspecific) as the conditioning stimulus (CS). Then, we re-expose the experimental animal to the CS rat the next day in a different context and assess social and escape behaviors in an escapable social interaction test (ESIT) that we have developed. We have observed that a session of conditioned social fear using our procedure produces increased avoidance behavior in the ESIT as well as increased aggressive behavior. The overall objective of this AREA proposal is to determine the neural circuitry involved in the alterations in social behavior produced by conditioned social fear in male and female rats. We will focus on the medial prefrontal cortex (mPFC) to bed nucleus of the stria terminalis (BNST) neuronal pathway. The BNST has been implicated in fear and anxiety and receives substantial input from the mPFC (Wood et al., 2018). Two primary subregions of the mPFC, the prelimbic cortex (PL) and the infralimbic cortex (IL) both project to the BNST, which is increasingly appreciated as a regulator of fear and anxiety. We propose that learned social fear/anxiety depends on the mPFC ? BNST neurocircuit and that the PL and IL inputs are separately involved in the distinct phases of social fear learning and memory: acquisition and extinction. We will use a cre- dependent intersectional chemogenetic approach to systematically inhibit or activate PL or IL neurons that project to the BNST, and we will test for alterations in social behavior (largely ignored in studies of fear and anxiety) in the ESIT as our dependent measure. We will also measure neuroplasticity-related proteins in this neural pathway using immunohistochemistry. These experiments will be the first to explore the contribution of the mPFC ? BNST circuitry in learned social fear/anxiety. Understanding the neural pathways involved in these phenomena will be valuable in the treatment of anxiety disorders that include a social component, such as SAD and PTSD. We propose to achieve our objectives with 2 Specific Aims. Aim 1 seeks to determine whether PL ? BNST neurons mediate acquisition of conditioned social fear. Aim 2 seeks to determine whether IL ? BNST neurons mediate extinction of conditioned social fear.