Our laboratory is interested in the biological basis of motivated behavior. Distributed neural circuits including the prefrontal cortex (PFC), the nucleus accumbens (NAc), the amygdala, the hippocampus; and multiple brainstem nuclei including the ventral tegmental area (VTA), locus ceruleus and the raphé nuclei are involved in the perception of salient environmental or internal stimuli and the processing of rewarding or aversive emotional and behavioral states in response to them.
Our laboratory studies how early life events, both genetic and environmental, impact upon subsequent brain and behavioral development. Among our particular interests are transgenic mouse models of human neurodevelopmental disorders relevant to autism, and determining how prenatal exposure to alcohol and drugs of abuse – both legal and illicit – may change liability for drug-seeking and consuming behaviors later in adolescence or adulthood.
Our recent work focuses on Gq-coupled GPCR-mediated (e.g., mAChR1, mGluR5) synaptic plasticity and how loss of the fragile X mental retardation protein (FMRP) may impact behavior, the role of μ-opioid receptor gene (OPRM1) polymorphisms in cellular signaling and behavioral responses to alcohol and opioid drugs, and the effects of prenatal alcohol exposure on GABAergic interneuron development and alcohol-related behavior in adulthood. We are also interested more broadly in translational pharmacotherapeutics, or how drugs with known mechanisms of action that are already FDA-approved for human use can be re-tasked for use in the treatment of neurodevelopmental or substance abuse disorders.
We use several different sets of methods to explore these questions.
While substance abuse neuroscientists use many behavioral methods, four are commonly used to investigate the acute responses and chronic adaptations to drugs of abuse: drug self-administration, intracranial self-stimulation (ICSS); conditioned place-preference (CPP); and locomotor sensitization. ICSS is a behavioral method in which animals are trained to perform a task to deliver direct electrical stimulation to brain reward circuitry. Drugs with abuse potential exert consistent, predictable effects on the rate and pattern of this operant response. In particular, all drugs of abuse, regardless of pharmacological class, potentiate the value of brain stimulation reward, or BSR. We measure ICSS in mice that have been prenatally exposed to cocaine or alcohol, or mice genetically modified to model human monogenic neurodevelopmental diseases relevant to autism, to investigate developmental changes in the pharmacology of this reward-based behavior. In addition to measuring operant or instrumental behaviors, such as drug self-administration and ICSS, we also address these developmental questions with behaviorally non-contingent, or Pavlovian, methods including locomotor sensitization and CPP.
Single-cell patch clamp electrophysiology in acute in vitro brain slices is a powerful tool for pharmacological dissection of synaptic mechanisms underlying the physiology – and pathophysiology – of disease states and neuroadaptive processes. We use this technique to address several questions, including: 1. whether in utero exposure to alcohol and other drugs of abuse or genetic mutations relevant to autism, such as fragile-X (Fmr1-), Angelman syndrome (Ube3am-/p+), or Rett syndrome (Mecp2-) alter the development of synaptic transmission in the VTA, NAc, and other elements of brain reward circuitry; 2. whether and how changes in synaptic plasticity are associated with such early developmental drug exposures or autism-related gene mutations; and 3. if and how alterations in the pharmacology of dopaminergic, opioidergic, cholinergic, or glutamatergic systems may explain some of these changes in neural circuit function and plasticity.
Design-based stereology is a quantitative anatomical tool that we use to investigate neural structure in animal models. Stereology is a method of systematic random sampling of structures of interest in a volume of tissue, eliminating the need to count all of the structures in that volume. Because this technique takes into consideration the volume of the brain region in question, densities of particular structures as well as absolute numbers of structures can be compared between experimental groups and controls. Since the counting frames are generated randomly by computer, there is less likelihood of investigator bias than counting numbers of structures per high-powered microscopic field. Also, because stereology takes into account the three-dimensional nature and geometry not only of the brain region of interest but also of the individual tissue sections, distributions of particular neural structures in space, such as dendritic arborizations, spines, or terminal projections, can be more rigorously estimated in an unbiased fashion, yielding more accurate insights into brain cytoarchitecture.