Subregional, Dendritic Compartment, and Spine Subtype Specificity in Cocaine Regulation of Dendritic Spines in the Nucleus Accumbens

Abstract

Numerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we employed single cell microinjections and advanced 3D imaging and analysis techniques to extend these findings in several important ways: by assessing cocaine regulation of dendritic spines in the core versus shell subregions of NAc in the mouse, over a broad time course (4 hours, 24 hours, or 28 days) of withdrawal from chronic cocaine, and with a particular focus on proximal versus distal dendrites. Our data demonstrate subregion-specific, and in some cases opposite, regulation of spines by cocaine on proximal but not distal dendrites. Notably, all observed density changes were attributable to selective regulation of thin spines. At 4 hours post-injection, the proximal spine density is unchanged in the core but significantly increased in the shell. At 24 hours, the density of proximal dendritic spines is reduced in the core but increased in the shell. Such down-regulation of thin spines in the core persists through 28 days of withdrawal, while the spine density in the shell returns to baseline levels. Consistent with previous results, dendritic tips exhibited up-regulation of dendritic spines after 24 hours of withdrawal, an effect localized to the shell. The divergence in regulation of proximal spine density in NAc core versus shell by cocaine correlates with recently reported electrophysiological data from a similar drug administration regimen and might represent a key mediator of changes in the reward circuit that drive aspects of addiction.

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

“…The selective increase in the frequency of spines with medium tip diameters (0.45-0.60 μm) in c-Fos+ neurons in the NAcc shell of Paired rats is similar to changes observed in this dendritic spine size in randomly selected neurons in the NAcc core following cocaine or exposure to discrete cues (Dumitriu et al, 2012;Gipson et al, 2013). Interestingly, Golgi-Cox staining used in previous studies is also most sensitive for detecting changes in these medium-sized spines (Shen et al, 2009).…”

“…Changes in overall dendritic spine (tip) density after the conditioning test were also analyzed using one-way ANOVAs (separately for c-Fos+ and c-Fos − neurons). Finally, spine tip diameters (for both ΔFosB and c-Fos studies) were measured across neurons and placed into bins to permit analytical comparisons to previously described results (Dumitriu et al, 2012;Shen et al, 2009). Two-way betweenwithin ANOVAs were performed to determine the presence Figure 1 Exposure to amphetamine IP (left) or in the VTA (right) enhances subsequent locomotor responding to amphetamine and ΔFosB expression in the NAcc.…”

“…Repeated administration of DA-releasing psychostimulant drugs produces both transient and long-lasting changes in the size and density of dendritic spines on these GABAergic neurons (Dumitriu et al, 2012;Kolb, 1997, 1999;Shen et al, 2009). These dendritic spines may be locations of memory storage in the brain (Lamprecht and LeDoux, 2004); various behavioral experiences have been shown to increase spine formation in vivo (Holtmaat et al, 2005(Holtmaat et al, , 2006Lai et al, 2012;Moczulska et al, 2013;Muñoz-Cuevas et al, 2013).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Although both NAcore and NAshell MSNs show similar general changes to treatment with cocaine, detailed evaluation suggests that cocaine differentially regulates synaptic plasticity between these two subregions in distal versus proximal dendrites (Dumitriu et al, 2012). For example, at 4 hours of withdrawal from cocaine injection, proximal spine density is increased in the shell but not core.…”

Possible contributions of a novel form of synaptic plasticity inAplysiato reward, memory, and their dysfunctions in mammalian brain

“…That regulation involves a variety of mechanisms, including activation of CREB and epigenetic changes in histone acetylation and methylation (Carlezon et al 1998;Brown et al 2011;Malvaez et al 2011;Maze et al 2011;Damez-Werno et al 2012;Sun et al 2012;Taniguchi et al 2012;Rogge et al 2013). In addition, drugs of abuse produce synaptic growth and structural changes related to L-LTP in NAc, including increases in dendritic branching, spine density, and spine size (Lee et al 2006;Ren et al 2010;Dobi et al 2011;Shen et al 2011;Dietz et al 2012;Dumitriu et al 2012;Gipson et al 2013a,b;Pitchers et al 2013;Robison et al 2013), as well as increases in pre-and postsynaptic proteins (Subramaniam et al 2001;Gipson et al 2013b). The drugs produce the same types of structural changes in PFC as well Kolb 1997, 1999;Robinson et al 2001;Hamilton et al 2010;Gourley et al 2012).…”