Background In utero alcohol, or ethanol, exposure produces developmental abnormalities in the brain of the fetus, which can result in lifelong behavioral abnormalities. Fetal alcohol spectrum disorders (FASD) is a term used to describe a range of adverse developmental conditions caused by ethanol exposure during gestation. Children diagnosed with FASD potentially exhibit a host of phenotypes including growth retardation, facial dysmorphology, central nervous system anomalies, abnormal behavior and cognitive deficits. Previous research suggests that abnormal gene expression and circuitry in the neocortex may underlie reported disabilities of learning, memory, and behavior resulting from early exposure to alcohol (El Shawa et al., 2013). Methods Here, we utilize a mouse model of FASD to examine effects of prenatal ethanol exposure, or PrEE, on brain anatomy in newborn (P0), weanling (P20) and early adult (P50) mice. We correlate abnormal cortical and subcortical anatomy with atypical behavior in adult P50 PrEE mice. In this model, experimental dams self-administered a 25% ethanol solution throughout gestation (gestational day, GD, 0 to 19, day of birth), generating the exposure to the offspring. Results Results from these experiments reveal long-term alterations to cortical anatomy, including atypical developmental cortical thinning, and abnormal subcortical development as a result of in utero ethanol exposure. Furthermore, offspring exposed to ethanol during the prenatal period performed poorly on behavioral tasks measuring sensorimotor integration and anxiety. Conclusions Insight from this study will help provide new information on developmental trajectories of prenatal ethanol exposure and the biological etiologies of abnormal behavior in people diagnosed with FASD.

The ontogenetic profile of psychostimulant-induced one-trial behavioral sensitization has not been determined. The purpose of this study was to systematically assess the ontogeny of methamphetamine- and cocaine-induced behavioral sensitization across the preweanling and adolescent periods. To this end, rats were injected with methamphetamine, cocaine, or saline in either an activity chamber or home cage during the preweanling (PD 12, PD 16, or PD 20), preadolescent (PD 24), or adolescent (PD 34) periods. One day later, rats were challenged with the same psychostimulant and locomotion was measured in an activity chamber. Results showed that methamphetamine produced one-trial locomotor sensitization on PD 13 and PD 17; whereas, cocaine-induced behavioral sensitization was only evident on PD 21. The sensitized responding of preweanling rats was not influenced by environmental context. Interestingly, preadolescent and adolescent rats did not exhibit locomotor sensitization. The latter result is generally consistent with past studies showing that rats from the middle and late adolescent periods do not exhibit cocaine-induced one-trial behavioral sensitization. The present results show that methamphetamine, as well as cocaine, can produce one-trial context-independent behavioral sensitization during early ontogeny, but sensitized responding is only apparent within a narrow developmental window.

Rationale Preweanling rats exhibit robust one-trial cocaine-induced behavioral sensitization; however, it is uncertain whether other psychostimulants can also induce sensitization in young rats using the one-trial procedure. Objective The purpose of this study was to determine whether methamphetamine, methylphenidate, and D-amphetamine are capable of inducing one-trial locomotor sensitization in preweanling rats. Methods In a series of four experiments, rats were pretreated with cocaine (30 mg/kg), methamphetamine (2–12 mg/kg), methylphenidate (5–20 mg/kg), or amphetamine (5 mg/kg) before being placed in a novel activity chamber or the home cage on PD 19. Rats were then challenged with the same psychostimulant (20 mg/kg cocaine, 1–8 mg/kg methamphetamine, 2.5–7.5 mg/kg methylphenidate, or 1–2 mg/kg amphetamine) on PD 21, with distance traveled being measured for 180 min. In a separate experiment, rats were pretreated with methamphetamine on PD 16–19 and challenged with methamphetamine on PD 21. Results Only cocaine, but not various dose combinations of other psychostimulants, was able to produce one-trial behavioral sensitization in preweanling rats. Context-dependent locomotor sensitization was also evident if rats were pretreated with methamphetamine on PD 16–19 and tested on PD 21. Conclusions It is uncertain why only cocaine was able to induce one-trial locomotor sensitization in preweanling rats, but it is possible that: (a) the neural circuitry mediating sensitization differs according to psychostimulant, (b) cocaine is more readily associated with environmental contexts than other psychostimulants, or (c) affinity and pharmacokinetic factors may underlie cocaine’s ability to induce one-trial behavioral sensitization in preweanling rats.

Prenatal ethanol exposure (PrEE) produces developmental abnormalities in brain and behavior that often persist into adulthood. We have previously reported abnormal cortical gene expression, disorganized neural circuitry along with deficits in sensorimotor function and anxiety in our CD-1 murine model of fetal alcohol spectrum disorders, or FASD (El Shawa et al., 2013; Abbott et al., 2016). We have proposed that these phenotypes may underlie learning, memory, and behavioral deficits in humans with FASD. Here, we evaluate the impact of PrEE on fear memory learning, recall and amygdala development at two adult timepoints. PrEE alters learning and memory of aversive stimuli; specifically, PrEE mice, fear conditioned at postnatal day (P) 50, showed deficits in fear acquisition and memory retrieval when tested at P52 and later at P70–P72. Interestingly, this deficit in fear acquisition observed during young adulthood was not present when PrEE mice were conditioned later, at P80. These mice displayed similar levels of fear expression as controls when tested on fear memory recall. To test whether PrEE alters development of brain circuitry associated with fear conditioning and fear memory recall, we histologically examined subdivisions of the amygdala in PrEE and control mice and found long-term effects of PrEE on fear memory circuitry. Thus, results from this study will provide insight on the neurobiological and behavioral effects of PrEE and provide new information on developmental trajectories of brain dysfunction in people prenatally exposed to ethanol.

During adulthood, associative learning is necessary for the expression of one-trial behavioral sensitization; however, it is uncertain whether the same associative processes are operative during the preweanling period. Two strategies were used to assess the importance of associative learning for the one-trial behavioral sensitization of preweanling rats. In the initial experiments, we varied both the sequence and time interval between presentation of the conditioned stimulus (CS, novel environment) and unconditioned stimulus (US, cocaine). In the final experiment, we determined whether ECS-induced retrograde amnesia would disrupt one-trial behavioral sensitization. Results showed that robust sensitized responding was apparent regardless of the sequence in which cocaine and the novel environment (the presumptive CS) were presented. Varying the time between CS and US presentation (0, 3, or 6 h) was also without effect. Results from Experiment 3 showed that single or multiple ECS treatments did not alter the expression of the sensitized response. Therefore, these data indicated that the one-trial behavioral sensitization of preweanling rats was exclusively mediated by nonassociative mechanisms and that associative processes did not modulate sensitized responding. These findings are in contrast to what is observed during adulthood, because adult rats exhibit one-trial behavioral sensitization only when associative processes are operative.