Pilot Project 1: Effects of adolescent alcohol exposure on maternal adaptations
PI: Joanna Workman (firstname.lastname@example.org)
Adolescence is a period of significant brain maturation and vulnerability to environmental factors. Alcohol exposure during adolescence induces persistent and widespread changes in brain and behavior including diminished behavioral flexibility, increased anxiety-like behavior and increased hypothalamic-pituitary-adrenal axis function. Importantly, the DA system is critical in maternal responsiveness and care of offspring. Further, maternal experience promotes DA-dependent attentional set shifting and induces a suite of behavioral and neural changes thought to be indirectly related to offspring fitness. It is possible that the long-term effects of adolescent alcohol exposure in females are particularly relevant during the postpartum period, when reorganization of the DA system is required for maternal responsiveness and care of offspring. Our overall hypothesis is that adolescent alcohol exposure interferes with the establishment of maternal behaviors and other maternal adaptations characteristic of postpartum rats. In Aim 1, we will test the hypotheses that adolescent alcohol exposure 1) impairs maternal care (licking and grooming, nursing), and 2) diminishes activation of the NAcc and VTA (particularly, DA-containing cells) in response to offspring exposure. In Aim 2, we will test the hypotheses that adolescent alcohol exposure 1) increases anxiety-like behavior in the elevated plus maze, 2) increases depression-like behavior in the forced swim test, 3) increases corticosterone responses to stressors and 4) reduces synapse density in the hippocampus and PFC in postpartum rats. This work will be critical for understanding how experiences prior to the postpartum period could alter the risk for neuropsychiatric illnesses.
Pilot Project 2: Neurodevelopmental consequences of binge alcohol drinking on fear extinction expression and medial prefrontal cortex plasticity.
PI: Hadley Bergstrom (email@example.com)
Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) often co-occur. Alcohol use tends to increase following PTSD, and in those with a comorbid AUD, the severity of traumatic fear symptoms can be worse. This makes alcohol a potential contributing factor in PTSD symptomatology. Despite the clear relationship between excessive alcohol use and PTSD symptomatology, the mechanistic interactions remain unknown. It is well-established that both traumatic fear and alcohol exposure produce lasting neuroadaptations that alter medial prefrontal cortex (mPFC) functioning. A growing body of evidence indicates that continued maturational changes in the mPFC render adolescents especially vulnerable to the neurobehavioral effects of both EtOH and traumatic stimuli. Further, males and females are differentially susceptible to EtOH effects and stress-related disorders. Together, these data indicate that age (adolescence versus adult) and sex may be interacting factors in how alcohol and traumatic stimuli produce neuroadaptations in the mPFC. The primary aim of this DEARC pilot project is to delineate the age- and sex-dependent neurobehavioral effects of chronic EtOH on fear extinction performance and mPFC plasticity. The proposed series of experiments tests the neurodevelopmental impact of EtOH exposure on fear extinction retrieval and medial prefrontal cortex (mPFC) plasticity using a novel social drinking-in-the-dark (binge) EtOH drinking paradigm, Pavlovian auditory cued fear conditioning and extinction, immunohistochemistry for the activity-regulated cytoskeletal protein Arc/arg3.1 (Arc) in the mPFC, and the Golgi-Cox stain to visualize mPFC dendrite and spine plasticity in a commonly used mouse strain (C57BL/6N; B6). It is anticipated that these experiments will provide key initial insights into how the expression of an established fear extinction memory may be modified by binge alcohol exposure and the relationship between extinction performance and alcohol-induced neuroadaptation in the mPFC.
Pilot Project 3: The role of enhanced inhibitory signaling within the insular cortex on increased alcohol use disorder liability following adolescent intermittent ethanol consumption
Adolescent intermittent ethanol consumption (AIE) results in a persistence of adolescent-typical alcohol-directed behaviors in adulthood which may underlie the enhanced liability for alcohol use disorders (AUDs) observed following AIE. Recent work demonstrates that AIE results in an increase in the presenceof perineuronal nets (PNNs) surrounding GABAergic interneurons within the insular cortex. These PNNs serve to increase inhibitory signaling through increased activation of interneurons which ultimately results in a decrease in both synaptic plasticity and a decrease in the output of glutamatergic projection neurons. Multiple prior studies have revealed that increased insular cortical inhibition and overall insular dysfunction underlie a number of behaviors associated with problematic alcohol use. In the present studies, we propose to use pharmacological and chemogenetic methods to limit the activity of insular GABAergic interneurons following AIE. We specifically propose to test that dissolution of PNNs and chemogenetic silencing of GABA neurons will rescue a number of the persistent adolescent-like alcohol-directed behaviors observed following AIE. Finally, we also propose to chemogenetically disconnect two insular corticofugal pathways in order to demonstrate that circuit-specific inhibition of insular outputs is sufficient to engender adolescent-like alcohol seeking phenotypes. Completion of these studies will accomplish two goals. The first will be to further our understanding of the neural mechanisms contributing to the enhanced liability for alcohol use disorders observed following use of alcohol during adolescence, particularly those within the insular cortex. The second is to allow us to generate substantial preliminary behavioral data for an upcoming NIAAA R01 submission examining how distinct insular GABAergic interneurons and IC circuits contribute to the development of AUDs in adolescents and adults.
Pilot Project 4: Impact of AIE exposure on pain sensitivity following sciatic nerve injury in adulthood
PI: Anushree Karkhanis (firstname.lastname@example.org)
Adolescence is a critical developmental period and insults during this period, such as excessive alcohol exposure, could potentially result in disruption of typical neural development, further dysregulating neural and perceptual processing, such as heightened pain sensitivity. Pain and alcohol use disorder (AUD) are highly comorbid and the causal relationship between the two is largely bidirectional: Alcohol use has been shown to be a risk factor for chronic pain potentially due to alcohol-induced neuroadaptations, and pain motivates alcohol consumption. Alcohol is known to interact with the mu opioid receptor (MOR) system, a major target system for pain management. Specifically, ethanol dependence is associated with attenuated MOR function. Thus, it is possible that sub-threshold function of MORs potentially inhibits endogenous regulation of pain as well as increases the difficulty of pain management further leading to exacerbated pain sensitivity. In Aim 1, we will establish an adolescent intermittent ethanol (AIE) exposure – chronic pain model. Particularly, we will determine the sensitivity to thermal nociception and mechanical allodynia/hyperalgesia in adult rats exposed to AIE. We predict that AIE exposed rats with exhibit enhanced sensitivity to thermal nociception and hyperalgesia compared to air exposed control rats. In Aim 2, we will clarify whether this alteration in nociceptive sensitivity and allodynia are driven by attenuated MOR function and can be reversed by a MOR agonist. We predict that MOR-agonist therapy will alleviate the enhanced sensitivity to thermal and mechanical stimuli. Completion of this study will accomplish three goals: First, we will establish a model of AIE and pain. Second, we will identify a possible therapeutic target, particularly MORs. Third, data collected from this study will be used to develop an R01 examining the mechanisms involved in driving comorbid AUD and chronic pain.
We anticipate funding additional Pilot projects annually. For more information on how to apply, click here.