Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms.

BACKGROUND AND PURPOSE: Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. EXPERIMENTAL APPROACH: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood-brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. KEY RESULTS: In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood-brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT2A-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. CONCLUSIONS AND IMPLICATIONS: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.

Effect of oral tryptamines on the gut microbiome of rats-a preliminary study.

Background: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.

The attenuation of activity-based anorexia by obese adipose tissue transplant is AgRP neuron-dependent.

Anorexia nervosa (AN) is an eating disorder observed primarily in girls and women, and is characterized by a low body mass index, hypophagia, and hyperactivity. The activity-based anorexia (ABA) paradigm models aspects of AN, and refers to the progressive weight loss, hypophagia, and hyperactivity developed by rodents exposed to time-restricted feeding and running wheel access. Recent studies identified white adipose tissue (WAT) as a primary location of the 'metabolic memory' of prior obesity, and implicated WAT-derived signals as drivers of recidivism to obesity following weight loss. Here, we tested whether an obese WAT transplant could attenuate ABA-induced weight loss in normal female mice. Recipient mice received a WAT transplant harvested from normal chow-fed, or HFD-fed obese mice; obese fat recipient (OFR) and control fat recipient (CFR) mice were then tested for ABA. During ABA, OFR mice survived longer than CFR mice, defined as maintaining 75% of their initial body weight. Next, we tested whether agouti-related peptide (AgRP) neurons, which regulate feeding behavior and metabolic sensing, mediate this effect of obese WAT transplant. CFR and OFR mice received either control or neonatal AgRP ablation, and were assessed for ABA. OFR intact mice maintained higher body weights longer than CFR intact mice, and this effect was abolished by neonatal AgRP ablation; further, ablation reduced survival in OFR, but not CFR mice. In summary, obese WAT transplant communicates with AgRP neurons to increase body weight maintenance during ABA. These findings encourage the examination of obese WAT-derived factors as potential treatments for AN.

Differential consumption of alcohol, caffeine, and caffeinated alcohol by adolescent rats, and effects on post-adolescent gene expression signatures in the nucleus accumbens and orbitofrontal cortex.

Caffeinated alcoholic beverages (CABs) are widely consumed despite little known about their behavioral and biological effects. Furthermore, CABs are also popular among adolescents, a particularly vulnerable and maturing demographic. In this preliminary study, we compared levels of daily adolescent voluntary consumption of caffeine (0.03%), alcohol (10%), caffeinated alcohol (0.03% + 10%), or vehicle and evaluated the effects of this on mRNA expression in brain regions associated with addiction and known to be affected by each drug. Beginning on postnatal day 30, rats were allowed unrestricted access to gelatin combined with one, both, or neither drug for twenty days. Compared to vehicle-consuming animals, consumption of gelatin was significantly attenuated when alcohol was included. The addition of caffeine to alcohol increased alcohol consumption in the early days of access compared to alcohol alone; however, after two weeks, alcohol consumption between these groups reached comparable levels. Compared to animals consuming caffeine alone, combining caffeine with alcohol significantly reduced caffeine intake. Targeted mRNA analysis of tissue collected from the nucleus accumbens and orbitofrontal cortex after the consumption period identified unique patterns of differentially expressed genes between treatment groups, across a broad array of neurotransmitter systems. Of particular note were genes related to a number of solute transporters and serotonergic functions. This preliminary work suggests unique pharmacological and behavioral effects from consuming caffeinated alcohol during adolescence. Since CABs are widely consumed by adolescents, these results suggest that more research into the pharmacological and behavioral effects elicited by CABs is warranted.

Muscle activity prior to experiencing the rubber hand illusion is associated with alterations in perceived hand location.

The rubber hand illusion (RHI) is a perceptual illusion in which one is made to feel that a hand-shaped object is part of their body. This illusion is believed to be the result of the integration of afferent information. However, there has been an increasing amount of evidence that suggests efferent information plays a role in this illusion as well. Previous research has found that individuals who are afflicted by pathological lack of movement experience the RHI more vividly than control participants. Whereas individuals who move their hands more than the general population (i.e. professional pianists) experience the RHI less vividly than control participants. Based upon the available evidence it would seem that muscle activity prior to experiencing the RHI should be associated with how vividly one experiences different indices of the illusion. In the present study we tested this possibility by having participants perform a maximum voluntary muscle contraction task prior to experiencing three variants of the RHI (moving active, moving passive and classic). It was found that electromyographic features known to be indicative of muscle fatigue exhibited a positive association with proprioceptive drift when stimulation was synchronous or visual movement only (with the exception of the passive moving RHI synchronous condition). More work is needed to better characterize the muscular processes associated with experiencing the RHI.

Effect of psilocybin on decision-making and motivation in the healthy rat.

Psilocybin and its active metabolite psilocin are hallucinogenic serotonergic agonists with high affinity for several serotonin receptors. In addition to underlying the hallucinogenic effects of these compounds, serotonin receptor activation also has important effects on decision-making and goal-directed behaviors. The impact of psilocybin and psilocin on these cognitive systems, however, remains unclear. This study investigated the effects of psilocybin treatment on decision-making and motivation in healthy male and female rats. We compared probability and delay discounting performance of psilocybin treated (1 mg/kg) to vehicle rats (n = 10/sex/group), and further assessed motivation in each group using a progressive ratio task. We also confirmed drug action by assessing head twitch responses after psilocybin treatment (1 mg/kg). Results from this study demonstrated that exposure to 1 mg/kg psilocybin did not affect decision-making in the probability and delay discounting tasks and did not reduce response rates in the progressive ratio task. However, psilocybin treatment did cause the expected increase in head twitch responses in both male and female rats, demonstrating that the drug was delivered at a pharmacologically relevant dosage. Combined, these results suggest that psilocybin may not impair or improve decision-making and motivation. Considering recent interest in psilocybin as a potential fast-acting therapeutic for a variety of mental health disorders, our findings also suggest the therapeutic effects of this drug may not be mediated by changes to the brain systems underlying reward and decision-making. Finally, these results may have important implications regarding the relative safety of this compound, suggesting that widespread cognitive impairments may not be seen in subjects, even after chronic treatment.

Development of an E. coli-based norbaeocystin production platform and evaluation of behavioral effects in rats.

Interest in the potential therapeutic efficacy of psilocybin and other psychedelic compounds has escalated significantly in recent years. To date, little is known regarding the biological activity of the psilocybin pathway intermediate, norbaeocystin, due to limitations around sourcing the phosphorylated tryptamine metabolite for in vivo testing. To address this limitation, we first developed a novel E. coli platform for the rapid and scalable production of gram-scale amounts of norbaeocystin. Through this process we compare the genetic and fermentation optimization strategies to that of a similarly constructed and previously reported psilocybin producing strain, uncovering the need for reoptimization and balancing upon even minor genetic modifications to the production host. We then perform in vivo measurements of head twitch response to both biosynthesized psilocybin and norbaeocystin using both a cell broth and water vehicle in Long-Evans rats. The data show a dose response to psilocybin while norbaeocystin does not elicit any pharmacological response, suggesting that norbaeocystin and its metabolites may not have a strong affinity for the serotonin 2A receptor. The findings presented here provide a mechanism to source norbaeocystin for future studies to evaluate its disease efficacy in animal models, both individually and in combination with psilocybin, and support the safety of cell broth as a drug delivery vehicle.

Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice.

Anorexia nervosa (AN) is an eating disorder observed predominantly in women and girls that is characterized by a low body-mass index, hypophagia, and hyperactivity. Activity-based anorexia (ABA), which refers to the weight loss, hypophagia, and hyperactivity exhibited by rodents exposed to both running wheels and scheduled fasting, provides a model for aspects of AN. Increased dopamine D2/D3 receptor binding in the anteroventral striatum has been reported in AN patients. We virally overexpressed D2Rs on nucleus accumbens core (D2R-OENAc) neurons that endogenously express D2Rs, and tested mice of both sexes in the open field test, ABA paradigm, and intraperitoneal glucose tolerance test (IGTT). D2R-OENAc did not alter baseline body weight, but increased locomotor activity in the open field across both sexes. During constant access to food and running wheels, D2R-OENAc mice of both sexes increased food intake and ran more than controls. However, when food was available only 7 h a day, only female D2R-OENAc mice rapidly lost 25% of their initial body weight, reduced food intake, and substantially increased wheel running. Surprisingly, female D2R-OENAc mice also rapidly lost 25% of their initial body weight during scheduled fasting without wheel access and showed no changes in food intake. In contrast, male D2R-OENAc mice maintained body weight during scheduled fasting. D2R-OENAc mice of both sexes also showed glucose intolerance in the IGTT. In conclusion, D2R-OENAc alters glucose metabolism in both sexes but drives robust weight loss only in females during scheduled fasting, implicating metabolic mechanisms in this sexually dimorphic effect.

Central but not peripheral oxytocin administration reduces risk-based decision-making in male rats.

The hormone oxytocin has long been associated with social behaviors, but recent evidence suggests that it may also affect reward processing in non-social contexts. Decisions are an integral component of many social and reward-based behavioral paradigms. Thus, a broad role for oxytocin in decision-making may explain the wide variety of effects that have been previously observed and resolve controversies in the literature about its role. To determine if oxytocin can selectively modulate decision-making in male rats, we assessed the dose-dependent effects of central (intracerebroventricular) or peripheral (intraperitoneal) administration of oxytocin on probability and delay discounting, two commonly used decision-making tasks that are free of social contexts. Our results showed that central administration of oxytocin dose-dependently reduced preference for risky outcomes in the probability discounting task, but had no impact on delay discounting or reward sensitivity. This effect was blocked by the co-administration of an oxytocin antagonist. Additionally, we found no effect of peripheral oxytocin administration on any task. To identify potential cognitive mechanisms of central oxytocin's effect on decision-making, we determined if central or peripheral oxytocin affects reward sensitivity using an intracranial self-stimulation task, and motivation using a progressive ratio task. These results showed that at the dosage that affects decision-making, central oxytocin had a mild and short-lasting effect on motivation, but no observable effect on reward sensitivity. This pattern of results suggests that oxytocin may selectively reduce risky decisions in male rats, even at dosages that have no major effects on reward processing and motivation. These findings highlight a potentially novel role for oxytocin in non-social cognitive processes and expand our understanding of the mechanism by which oxytocin may regulate social behavior.

Extent of food restriction affects probability but not delay-based decision-making.

Rodent studies on decision-making often use food rewards and food-restrict subjects in order to motivate performance. However, food restriction has widespread effects on brain and behavior, which depend on factors including extent of restriction and feeding schedule. These factors are well recognized for their effects on motivation, but may also cause effects on decision-making independent of motivation. We examined how the degree of weight-based food restriction in rats influenced decision-making on the probability and delay discounting tasks. Additionally, we examined how the method of food restriction (consistent amount vs. time constrained feeding schedule) influenced decision-making. Our results showed that the degree of weight-based food restriction significantly altered probability, but not delay discounting, and that these effects were not entirely explainable by differences in motivation. Additionally, the method of food restriction did not significantly influence discounting when animals were within the same range of weight-based restriction. Together, our findings suggest that the degree of food restriction may modulate the neural circuitry responsible for selective aspects of decision-making related to probability. Further, these data support the need for tight control and reporting of weight and feeding in studies relying on food restriction, and suggest that the effects of food restriction may be broader than previously considered.

Integrating Research into the Undergraduate Curriculum: 1. Early Research Experiences and Training.

Undergraduate research experiences have emerged as some of the most beneficial high-impact practices in education, providing clear benefits to students that include improved critical thinking and scientific reasoning, increased academic performance, and enhanced retention both within STEM majors and in college overall. These benefits extend to faculty members as well. Several disciplines, including neuroscience, have implemented research as part of their curriculum, yet many research opportunities target late stage undergraduates, despite evidence that early engagement can maximize the beneficial nature of such work. A 2019 Society for Neuroscience professional development workshop provided multiple examples of integrating research into an undergraduate curriculum, including early engagement (Fernandes, 2020). This article is the first in a series of three that expands upon the information presented in those workshop discussions, focusing on ways to promote early research opportunities. The benefits and challenges associated with early research engagement suggest thoughtful consideration of the best mechanisms for implementation are warranted; some options might include apprenticeship models or course-based approaches. Regardless of mechanism, early research can serve to initiate more prolonged, progressive, scaffolded experiences that span the academic undergraduate career.

Integrating Research into the Undergraduate Curriculum: 2. Scaffolding Research Skills and Transitioning toward Independent Research.

Undergraduate research experiences are widely regarded as high-impact practices that foster meaningful mentoring relationships, enhance retention and graduation, and stimulate postbaccalaureate enrollment in STEM graduate and professional programs. Through immersion in a mentored original research project, student develop and apply their skills in critical thinking, problem solving, intellectual independence, communication, collaboration, project ownership, innovation, and leadership. These skills are readily transferable to a wide array of future careers in and beyond STEM that are well-served by evidence-based approaches. The 2019 Society for Neuroscience meeting included a well-attended workshop on integrating research into the curriculum at primarily undergraduate institutions (PUIs). This article is the second of three articles that summarize, analyze, and expand the workshop discussions. In this second article, we specifically describe approaches to transitional research courses that prepare students for independent research experiences such as undergraduate research theses. Educators can intentionally scaffold research experience and skills across the curriculum, to foster participation in scientific research and enhance diversity, equity, and inclusivity in research training. This article provides an overview of important goals and considerations for intermediate undergraduate research experiences, specific examples from several institutions of transitional courses that scaffold research preparation using different structures, and a summary of lessons learned from these experiences.

The effects of multiple early life stressors on adolescent alcohol consumption.

Alcohol use disorder is pervasive and effects the health of millions. Identifying factors such as early life stress that contribute to the development of alcohol use disorder is therefore critical, especially those that contribute to adolescent drinking, a strong predictor of AUD development. The majority of prior studies have examined early life effects on adult drinking, but have not studied intake during adolescence, and no prior studies have examined how the effects of multiple stressors may be additive. Therefore, this study determined if experiencing individual or multiple stressors increases adolescent alcohol intake. Male Long Evans rats underwent either early or late maternal separation (postnatal day 2-9 or 13-20), early adolescent social defeat (PND 30-40), both, or neither. All rats were then given two-hour access to alcohol, and voluntary intake assessed daily in late adolescence (PND 41-51). In adulthood, sensitivity to alcohol's sedative effects was assessed using loss and regain of righting reflex tests. Results indicate that experiencing maternal separation (at either time point) or social defeat increased adolescent alcohol consumption, but experiencing the combined stressors did not, and that no stressor significantly affected body weight during adolescence or loss and regain of righting reflex in adulthood. Overall, this pattern of effects suggests that experiencing any individual early life stressor may increase adolescent alcohol intake, in agreement with prior literature, but that the combined effects of multiple early life stressors may be more complicated.

Brain Stimulation Reward Supports More Consistent and Accurate Rodent Decision-Making than Food Reward.

Animal models of decision-making rely on an animal's motivation to decide and its ability to detect differences among various alternatives. Food reinforcement, although commonly used, is associated with problematic confounds, especially satiety. Here, we examined the use of brain stimulation reward (BSR) as an alternative reinforcer in rodent models of decision-making and compared it with the effectiveness of sugar pellets. The discriminability of various BSR frequencies was compared to differing numbers of sugar pellets in separate free-choice tasks. We found that BSR was more discriminable and motivated greater task engagement and more consistent preference for the larger reward. We then investigated whether rats prefer BSR of varying frequencies over sugar pellets. We found that animals showed either a clear preference for sugar reward or no preference between reward modalities, depending on the frequency of the BSR alternative and the size of the sugar reward. Overall, these results suggest that BSR is an effective reinforcer in rodent decision-making tasks, removing food-related confounds and resulting in more accurate, consistent, and reliable metrics of choice.

Acute and long-term effects of adolescent methylphenidate on decision-making and dopamine receptor mRNA expression in the orbitofrontal cortex.

Though commonly used as a treatment for ADHD, the psychostimulant methylphenidate (MPH) is also misused and abused in adolescence in both clinical and general populations. Although MPH acts via pathways activated by other drugs of abuse, the short- and long-term effects of MPH on reward processing in learning and decision-making are not clearly understood. We examined the effect of adolescent MPH treatment on a battery of reward-directed behaviors both in adolescence during its administration and in adulthood after its discontinuation. We further measured whether MPH had lasting effects on dopamine receptor mRNA expression in orbitofrontal cortex (OFC) that may correspond with behavior. Long-Evans rats were injected with MPH (0, 1, 2.5, or 5mg/kg IP) twice daily from middle to late adolescence (PD38-57). During adolescence, the high dose of MPH reduced preference for large rewards in a Reward Magnitude Discrimination task, but did not affect preference for smaller-sooner rewards in a Delay Discounting task. In adulthood, after discontinuation of MPH, animals previously treated with the moderate dose of MPH showed improved acquisition, but not reversal, in a Reversal Learning task. MPH exposure did not increase preference for large-risky rewards in a Risk task in adulthood. We then quantified mRNA expression of D1, D2, and D3 receptors in the OFC using qPCR. MPH increased mRNA expression of dopamine D3 receptor subtype, but not D1 or D2. Overall, these results indicate that MPH has both immediate and lasting effects on reward-dependent learning and decisions, as well as dopaminergic function in rodents.

Maternal buffering beyond glucocorticoids: impact of early life stress on corticolimbic circuits that control infant responses to novelty.

Maternal presence has a potent buffering effect on infant fear and stress responses in primates. We previously reported that maternal presence is not effective in buffering the endocrine stress response in infant rhesus monkeys reared by maltreating mothers. We have also reported that maltreating mothers show low maternal responsiveness and permissiveness/secure-base behavior. Although still not understood, it is possible that this maternal buffering effect is mediated, at least partially, through deactivation of amygdala response circuits when mothers are present. Here, we studied rhesus monkey infants that differed in the quality of early maternal care to investigate how this early experience modulated maternal buffering effects on behavioral responses to novelty during the weaning period. We also examined the relationship between these behavioral responses and structural connectivity in one of the underlying regulatory neural circuits: amygdala-prefrontal pathways. Our findings suggest that infant exploration in a novel situation is predicted by maternal responsiveness and structural integrity of amygdala-prefrontal white matter depending on maternal presence (positive relationships when mother is absent). These results provide evidence that maternal buffering of infant behavioral inhibition is dependent on the quality of maternal care and structural connectivity of neural pathways that are sensitive to early life stress.

Activity-Based Anorexia Alters the Expression of BDNF Transcripts in the Mesocorticolimbic Reward Circuit.

Anorexia nervosa (AN) is a complex eating disorder with severe dysregulation of appetitive behavior. The activity-based anorexia (ABA) paradigm is an animal model in which rodents exposed to both running wheels and scheduled feeding develop aspects of AN including paradoxical hypophagia, dramatic weight loss, and hyperactivity, while animals exposed to only one condition maintain normal body weight. Brain-derived neurotrophic factor (BDNF), an activity-dependent modulator of neuronal plasticity, is reduced in the serum of AN patients, and is a known regulator of feeding and weight maintenance. We assessed the effects of scheduled feeding, running wheel access, or both on the expression of BDNF transcripts within the mesocorticolimbic pathway. We also assessed the expression of neuronal cell adhesion molecule 1 (NCAM1) to explore the specificity of effects on BDNF within the mesocorticolimbic pathway. Scheduled feeding increased the levels of both transcripts in the hippocampus (HPC), increased NCAM1 mRNA expression in the ventral tegmental area (VTA), and decreased BDNF mRNA levels in the medial prefrontal cortex (mPFC). In addition, wheel running increased BDNF mRNA expression in the VTA. No changes in either transcript were observed in the nucleus accumbens (NAc). Furthermore, no changes in either transcript were induced by the combined scheduled feeding and wheel access condition. These data indicate that scheduled feeding or wheel running alter BDNF and NCAM1 expression levels in specific regions of the mesocorticolimbic pathway. These findings contribute to our current knowledge of the molecular alterations induced by ABA and may help elucidate possible mechanisms of AN pathology.

Effects of prenatal cocaine exposure on early postnatal rodent brain structure and diffusion properties.

Prenatal cocaine exposure has been associated with numerous behavioral phenotypes in clinical populations, including impulsivity, reduced attention, alterations in social behaviors, and delayed language and sensory-motor development. Detecting associated changes in brain structure in these populations has proven difficult, and results have been inconclusive and inconsistent. Due to their more controlled designs, animal models may shed light on the neuroanatomical changes caused by prenatal cocaine; however, to maximize clinical relevance, data must be carefully collected using translational methods. The goal of this study was two-fold: (1) to determine if prenatal cocaine alters developmental neuroanatomy using methods that are available to human researchers, specifically structural MRI and diffusion tensor imaging, and (2) to determine the feasibility of rodent in vivo neuroimaging for usage in longitudinal studies of developmental disorders. Cocaine-exposed (prenatal days 1-20, 30mg/kg/day) rat pups were sedated and imaged live using diffusion tensor imaging and postmortem (fixed) using magnetic resonance histology on postnatal day 14. Volume and diffusion properties in whole brain as well as specific regions of interest were then assessed from the resulting images. Whole brain analyses revealed that cocaine-exposed animals showed no change in whole brain volume. Additionally, we found alterations in fractional anisotropy across regions associated with reward processing and emotional regulation, especially in the thalamus and globus pallidus, as well as sex-dependent effects of cocaine in the right cortex. Reductions in fractional anisotropy were paired with reductions only in axial diffusivity, which preliminarily suggests that the changes observed here may be due to axonal damage, as opposed to reductions in myelination of the affected regions/pathways. Our data indicate that prenatal cocaine may target a number of developing brain structures but does not result in overt changes to brain volumes. These results highlight not only the brain alterations that result from prenatal cocaine but also the advancements in live imaging that allow longitudinal study designs in other models.

Translational analysis of effects of prenatal cocaine exposure on human infant cries and rat pup ultrasonic vocalizations.

Spectral and temporal features of human infant crying may detect neurobehavioral effects of prenatal cocaine exposure (PCE). Finding comparable measures of rodent ultrasonic vocalizations (USVs) would promote translational analyses by controlling the effects of correlated variables that confound human studies. To this end, two studies examined the sensitivity of similar acoustic structures in human infant and rat pup vocalizations to effects of PCE. In Study 1, cry sounds of 107 one month-old infants were spectrum analyzed to create a novel set of measures and to detect the presence of hyperphonation - a qualitative shift to an atypically high fundamental frequency (basic pitch) associated with neurobehavioral insult. Infants with PCE were compared to infants with prenatal polydrug-exposure (PPE) without cocaine and with infants in a standard comparison (SC) group with no prenatal drug exposure. In Study 2, USVs of 118 five day-old rat pups with either PCE, prenatal saline exposure or no prenatal exposures were spectrum analyzed to detect the presence of frequency shifts - acoustic features that have a frequency waveform similar to that of hyperphonation. Results of study 1 showed PCE had two sets of sex-dependent effects on human infants: PCE males had higher pitched cries with more dysphonation (turbulence); PCE females had longer pauses between fewer cry sounds that were of lower amplitude than comparison groups. PCE and PPE infants had more cries with hyperphonation than SC infants. In study 2, PCE pups had a greater percentage of USVs with shift in the acoustic structure than pups in the two control groups. As such, the novel measures of human infant crying and rat pup USVs were sensitive to effects of PCE. These studies provide the first known translational analysis of similar acoustic structures of vocalizations in two species to detect adverse effects of prenatal drug exposure.

Effects of voluntary alcohol intake on risk preference and behavioral flexibility during rat adolescence.

Alcohol use is common in adolescence, with a large portion of intake occurring during episodes of binging. This pattern of alcohol consumption coincides with a critical period for neurocognitive development and may impact decision-making and reward processing. Prior studies have demonstrated alterations in adult decision-making following adolescent usage, but it remains to be seen if these alterations exist in adolescence, or are latent until adulthood. Here, using a translational model of voluntary binge alcohol consumption in adolescents, we assess the impact of alcohol intake on risk preference and behavioral flexibility during adolescence. During adolescence (postnatal day 30-50), rats were given 1-hour access to either a 10% alcohol gelatin mixture (EtOH) or a calorie equivalent gelatin (Control) at the onset of the dark cycle. EtOH consuming rats were classified as either High or Low consumers based on intake levels. Adolescent rats underwent behavioral testing once a day, with one group performing a risk preference task, and a second group performing a reversal-learning task during the 20-day period of gelatin access. EtOH-High rats showed increases in risk preference compared to Control rats, but not EtOH-Low animals. However, adolescent rats did a poor job of matching their behavior to optimize outcomes, suggesting that adolescents may adopt a response bias. In addition, adolescent ethanol exposure did not affect the animals' ability to flexibly adapt behavior to changing reward contingencies during reversal learning. These data support the view that adolescent alcohol consumption can have short-term detrimental effects on risk-taking when examined during adolescence, which does not seem to be attributable to an inability to flexibly encode reward contingencies on behavioral responses.