Chronic Ethanol During Adolescence Impacts Corticolimbic Dendritic Spines and Behavior

Abstract

Background Risk for alcohol use disorders (AUDs) is linked to alcohol drinking during adolescence, but understanding of the neural and behavioral consequences of alcohol exposure during adolescence remains incomplete. Here, we examined the neurobehavioral impact of adolescent chronic intermittent EtOH (CIE) vapor exposure in mice. Methods C57BL/6J-background Thy1-EGFP mice were CIE-exposed during adolescence or adulthood and examined, as adults, for alterations in the density and morphology of dendritic spines in infralimbic cortex (IL), prelimbic cortex (PL) and basolateral amygdala (BLA). In parallel, adolescent- and adult-exposed C57BL/6J mice were tested as adults for two-bottle EtOH drinking, sensitivity to EtOH intoxication (loss of righting reflex, LORR), blood EtOH clearance, and measures of operant responding for food reward. Results CIE during adolescence decreased IL neuronal spine density and increased the head-width of relatively wide-head IL and BLA spines, whereas CIE decreased head-width of relatively narrow-head BLA spines. Adolescents had higher EtOH consumption prior to CIE than adults, while CIE during adulthood, but not adolescence, increased EtOH consumption relative to pre-CIE baseline. CIE produced a tolerance-like decrease in LORR sensitivity to EtOH challenge, irrespective of the age at which mice received CIE exposure. Mice exposed to CIE during adolescence, but not adulthood, required more sessions than AIR controls to reliably respond for food reward on a fixed-ratio (FR1), but not subsequent FR3, reinforcement schedule. On a progressive ratio reinforcement schedule, breakpoint responding was higher in the adolescent- than the adult-exposed mice, regardless of CIE. Finally, footshock-punishment markedly suppressed responding for reward in all groups. Conclusions Exposure to CIE during adolescence altered dendritic spine density and morphology in IL and BLA neurons, in parallel with a limited set of behavioral alterations. Together, these data add to growing evidence that key corticolimbic circuits are vulnerable to the effects of alcohol during adolescence, with lasting, potentially detrimental, consequences for behavior.

Prefrontal Regulation of Punished Ethanol Self-administration

“…We first examined the behavioral profile of mice undergoing in vivo neuronal recordings. Replicating previous observations (37)(38)(39), the rate of EtOH lever pressing was significantly suppressed during punishment and probe testing, compared with the unpunished baseline period of the punishment session ( Figure 1B, C). The number of shocks received inversely predicted suppression on probe (i.e., positive correlation between EtOH-SA during punishment and probe [r = .61, p = .003]), showing that the degree of suppression during probe testing was not due to the number of shocks received.…”

“…Mice were trained in a Med Associates operant chamber (Med Associates, Inc., Fairfax, VT) to respond on the left of two levers on a continuous schedule of reinforcement to earn sucrose pellets during 40-minute sessions (the right, "inactive" lever had no programed consequences) until the criterion was met ($35 rewards), as previously described (37)(38)(39). The pellet was then substituted with a progression of 10-mL liquid rewards ("sucrose fading"; 10% sucrose, 10% sucrose 1 10% EtOH, 5% sucrose 1 10% EtOH, 10% EtOH).…”

Adolescent Ethanol Exposure: Anxiety-Like Behavioral Alterations, Ethanol Intake, and Sensitivity

“…For instance, adult male rats exposed to ethanol during adolescence (P30-48, 1, 2, 3 or 4 g/kg ethanol, IP) and challenged with a hypnotic ethanol dose regained their righting reflex more rapidly than did their non-exposed counterparts (Matthews et al, 2008), with these alterations evident only following high exposure doses of ethanol (3 and 4 g/kg). These results were also replicated by the same group (Matthews et al, 2017) and others using mice (Jury et al, 2017). However, similar decreases in LORR duration were evident following adult exposure as well (Jury et al, 2017).…”

“…Many studies that reported increases in ethanol intake following adolescent ethanol exposure did not include other age groups for comparison. Of the studies that included adolescents and adults, previous exposure to ethanol tended to increased ethanol intake later in life regardless of exposure timing (Hefner and Holmes, 2007;Tambour et al, 2008;Strong et al, 2010;Carrara-Nascimento et al, 2013;O'Tousa et al, 2013;Amodeo et al, 2017) or following adult exposure only (Fullgrabe et al, 2007;Jury et al, 2017), suggesting that exposure-related increases in ethanol consumption may not be specific to adolescent exposure. Therefore, it is still not clear whether adolescents are more vulnerable than adults to ethanol-exposure-related increases in ethanol intake.…”

Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings

“…NADIA studies have found AIE alters adult dendritic spine density and shifts spine subtypes in multiple brain regions (Mulholland et al., ; Risher et al., ; Trantham‐Davidson et al., ), a finding that has recently been extended to mice (Jury et al., ). Dendritic spine changes are brain region–specific; for example, in the central and medial, but not basolateral amygdala, AIE exposure reduces total dendritic spine density (Jury et al., ; Pandey et al., ), whereas in medial PFC, AIE increases spine density (Trantham‐Davidson et al., ). The functional status of decreased dendritic spines in the amygdala in adulthood after AIE is not known.…”