Adolescent exposure to stimulants, such as cocaine, may permanently affect the coordinated development of the frontal cortex at the synaptic, circuit and behavioral level. The development of the frontal cortex takes place during late childhood and adolescence, a critical moment for the development for substance use (Paus et al., 2007; Chambers et al., 2003; Spear, 2000). Classic histological analysis and recent longitudinal anatomical structural imaging studies have shown that human frontal cortical development is highly dynamic during adolescence (Lewis et al.,1997;2008; Paus et al., 2008). Volatility of this period may create vulnerability to the development of addiction and serious mental health issues. Repeated stimulant exposure consistently enhances spine density in the apical dendrites of the medial prefrontal cortex in adult rodents (Robinson and Kolb, 2004). It is unclear if this effect is due to fewer synapses lost or more gained in the dynamic process of spine turnover which continues in the cortex through adulthood (Holtmaat et al., 2005). It is also unclear if these extra spines represent greater connectivity from the amygdala, the thalamus, or other regions that innervate frontal dendrites. Further work needs to be done to understand how stimulant exposure affects spine plasticity and synapse properties specifically during the volatile period of adolescent maturation. Our understanding also needs to be refined, so that we better understand the mechanisms of these synaptic changes and specificity to particular circuits. We are using multi-photon imaging technology to determine the effect of early and late adolescent binge cocaine exposure on spine structural dynamics in vivo (spine growth and loss, Aim1 ) and optogenetic technology to measure the balance of input from specific, isolated, long-range afferents that drive frontal cortex (Aim 2). We supplement these anatomical and functional studies of synapses with behavioral analysis to assess the function of the frontal cortex in mice exposed to cocaine at early and late stages of adolescence and saline controls (Aim 3). We will compare the short and long term effects of cocaine exposure on spine dynamics, synapses and behavior in both adolescent and adult mice. Our studies will illuminate the developmental synaptic and circuit mechanisms that make adolescence a high risk period for the development of substance use problems and will inform clinicians and stimulant users of possible negative impacts of use on specific frontal circuit synapses at different stages of development. By identifying specific circuits, synapses, and synaptic plasticity mechanisms that are disrupted by stimulant exposure, our data will also serve as a guide for selection and testing of future drug and cognitive therapies to ameliorate the negative effects of adolescent stimulant exposure on specific neural circuits in adult brains.

Public Health Relevance

Adolescent exposure to stimulants, such as cocaine, may permanently affect the coordinated development of the frontal cortex at the synaptic, circuit and behavioral level. We will measure the effect of cocaine exposure on in vivo spine dynamics, synapses and behavior in both adolescent and adult mouse models. By identifying specific circuits, synapses, and synaptic plasticity mechanisms that are disrupted, our data will also serve as a guide for selection and testing of future drug and cognitive therapies to repair the negative effects of adolescent stimulant exposure on adult neural circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA029150-07
Application #
8823749
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2013-07-01
Project End
2017-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
7
Fiscal Year
2015
Total Cost
$337,512
Indirect Cost
$122,536
Name
University of California Berkeley
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Boivin, Josiah R; Piekarski, David J; Thomas, A Wren et al. (2018) Adolescent pruning and stabilization of dendritic spines on cortical layer 5 pyramidal neurons do not depend on gonadal hormones. Dev Cogn Neurosci 30:100-107
Piekarski, David J; Boivin, Josiah R; Wilbrecht, Linda (2017) Ovarian Hormones Organize the Maturation of Inhibitory Neurotransmission in the Frontal Cortex at Puberty Onset in Female Mice. Curr Biol 27:1735-1745.e3
Piekarski, David J; Johnson, Carolyn M; Boivin, Josiah R et al. (2017) Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? Brain Res 1654:123-144
Johnson, Carolyn M; Loucks, F Alexandra; Peckler, Hannah et al. (2016) Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence. Dev Cogn Neurosci 18:113-20
Johnson, Carolyn M; Peckler, Hannah; Tai, Lung-Hao et al. (2016) Rule learning enhances structural plasticity of long-range axons in frontal cortex. Nat Commun 7:10785
Lee, A Moses; Tai, Lung-Hao; Zador, Anthony et al. (2015) Between the primate and 'reptilian' brain: Rodent models demonstrate the role of corticostriatal circuits in decision making. Neuroscience 296:66-74
Boivin, Josiah R; Piscopo, Denise M; Wilbrecht, Linda (2015) Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior. Neuropharmacology 97:404-13
Muñoz-Cuevas, Francisco Javier; Athilingam, Jegath; Piscopo, Denise et al. (2013) Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference. Nat Neurosci 16:1367-9
Tai, Lung-Hao; Lee, A Moses; Benavidez, Nora et al. (2012) Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value. Nat Neurosci 15:1281-9
Johnson, Carolyn; Wilbrecht, Linda (2011) Juvenile mice show greater flexibility in multiple choice reversal learning than adults. Dev Cogn Neurosci 1:540-51