Rodent models of prenatal alcohol exposure are a powerful tool for studying causal factors of prenatal exposure effects. Under the New Mexico Alcohol Research Center, we combined a voluntary drinking-in-the-dark (DID) paradigm with a Volumetric Drinking Monitor (VDM) system to quantify maternal ethanol (EtOH) intake, drinking duration, and drinking patterns throughout gestation and determined whether these variables altered breeding success or early offspring development. Female C57BL/6J mice received daily 2-h access to either 20% EtOH or water using the VDM system. Following a two-week acclimation period, breeding was initiated while daily drinking continued throughout gestation until parturition. Breeding success, litter characteristics, and early growth were evaluated from 176 dam-sire pairings across three breeding cohorts, yielding over 800 offspring for demographic analyses. Maternal EtOH exposure did not affect pregnancy success, litter loss, litter size, pup weight at postnatal day 10, offspring sex distribution, or weaning weight. Average daily gestational EtOH consumption and duration of preconception EtOH exposure did not predict offspring outcomes. Although EtOH-exposed dams consistently exhibited front-loading behavior, neither front-loading status nor front-loading intensity was associated with litter characteristics or early offspring growth. Moderate voluntary maternal EtOH consumption, duration of exposure, or drinking pattern did not drive litter characteristics that may affect the early-life environment (pup number and sex) or early growth markers (P10 and weaning weight). These data indicate that differences in the early postnatal environment are not likely to be responsible for long-term behavioral and neurobiological phenotypes reported in offspring produced using this paradigm.

It is well established that alcohol interacts with multiple molecular targets, including ligand- and voltage-gated ion channels and intracellular signal proteins, leading to molecular and cellular neuroadaptations in various brain regions, including the cerebral cortex, hippocampus, amygdala, and cerebellum [[1], [2], [3]]. Despite the extensive literature, little is known about the effects of alcohol in the posterior parietal cortex (PPC), a cortical region involved in multiple cognitive and executive functions [4,5]. Here, we report data showing the acute alcohol effects on neuronal excitability in pyramidal neurons and interneurons expressed in PPC. Briefly, whole-cell patch clamp recordings in current clamp mode were conducted in coronal brain slices containing PPC. Resting membrane potential, input resistance, action potential (AP) threshold, and frequency were assessed during baseline, following 10 minutes of bath application of alcohol 50 mM, and after 10 minutes of washout. The data show that alcohol negatively modulates the excitability of PPC at the cellular level, as we observed a significant decrease in input resistance and AP frequency, and an increase in rheobase in PPC interneurons. Furthermore, these effects persisted even after 10 minutes of washout, indicating sustained changes in neuronal excitability. Intriguingly, acute alcohol exposure did not alter the neuronal excitability in PPC pyramidal neurons. This set of electrophysiological data may be of interest to investigators who are studying how alcohol effects voltage-gated ion channels.

Wildland fires have become progressively more extensive over the past 30 years in the US, and now routinely generate smoke that deteriorates air quality for most of the country. We explored the neurometabolomic impact that smoke derived from biomass has on older (18 months) female C57BL/6J mice, both acutely and after 10 weeks of recovery from exposures. Mice (N=6/group) were exposed to wood smoke (WS) 4 hours/day, every other day, for 2 weeks (7 exposures total) to an average concentration of 0.448mg/m 3 per exposure. One group was euthanized 24 hours after the last exposure. Other groups were then placed on 1 of 4 treatment regimens for 10 weeks after wood smoke exposures: vehicle; resveratrol in chow plus nicotinamide mononucleotide in water (RNMN); senolytics via gavage (dasatanib+quercetin; DQ); or both RNMN with DQ (RNDQ). Among the findings, the aging from 18 months to 21 months was associated with the greatest metabolic shift, including changes in nicotinamide metabolism, with WS exposure effects that were relatively modest. WS caused a reduction in NAD+ within the prefrontal cortex immediately after exposure and a long-term reduction in serotonin that persisted for 10 weeks. The serotonin reductions were corroborated by forced swim tests, which revealed an increased immobility (reduction in motivation) immediately post-exposure and persisted for 10 weeks. RNMN had the most beneficial effects after WS exposure, while RNDQ caused markers of brain aging to be upregulated within WS-exposed mice. Findings highlight the persistent neurometabolomic and behavioral effects of woodsmoke exposure in an aged mouse model. Significance Statement:Neurological impacts of wildfire smoke are largely underexplored but include neuroinflammation and metabolic changes. The present study highlights modulation of major metabolites in the prefrontal cortex and behavioral consequences in aged (18 month) female mice that persists 10 weeks after wood smoke exposure ended. Supplements derived from the anti-aging field were able to mitigate much of the woodsmoke effect, especially a combination of resveratrol and nicotinamide mononucleotide.

The present chapter summarizes the clinical and preclinical findings collected to date, showing the impact of developmental alcohol exposure on sleep physiology. Sleep is a complex physiological process that plays a pivotal role in maintaining overall health and well-being via its involvement in regulating physiological, cognitive, and emotional functions. Clinical studies consistently report a high prevalence of sleep disturbances in children and adolescents diagnosed with fetal alcohol spectrum disorders (FASDs), including short sleep duration, sleep anxiety, bedtime resistance, increased sleep fragmentation, and parasomnias. It is established that alcohol consumption during gestation impairs brain development, leading to structural and functional alterations that may affect sleep architecture. In addition, clinical investigations have found a significant correlation between sleep-wake cycle disruptions and cognitive impairments after developmental alcohol exposure, and sleep disturbances are increasingly recognized as a substantial problem among FASD patients. However, the molecular mechanisms underlying these disturbances are poorly understood. Surprisingly, few studies with animal models of FASDs have characterized the effect of developmental ethanol exposure on sleep physiology, and these have focused on high doses. This chapter provides an overview of the current knowledge, reports the sleep disturbances in FASD patients, and then summarizes the gap in understanding the molecular and physiological mechanisms.

The vast majority of gene mutations and/or gene knockouts result in either no observable changes, or significant deficits in molecular, cellular, or organismal function. However, in a small number of cases, mutant animal models display enhancements in specific behaviors such as learning and memory. To date, most gene deletions shown to enhance cognitive ability generally affect a limited number of pathways such as NMDA receptor- and translation-dependent plasticity, or GABA receptor- and potassium channel-mediated inhibition. While endolysosomal trafficking of AMPA receptors is a critical mediator of synaptic plasticity, mutations in genes that affect AMPAR trafficking either have no effect or are deleterious for synaptic plasticity, learning and memory. NSG2 is one of the three-member family of Neuron-specific genes (NSG1-3), which have been shown to regulate endolysosomal trafficking of a number of proteins critical for neuronal function, including AMPAR subunits (GluA1-2). Based on these findings and the largely universal expression throughout mammalian brain, we predicted that genetic knockout of NSG2 would result in significant impairments across multiple behavioral modalities including motor, affective, and learning/memory paradigms. However, in the current study we show that loss of NSG2 had highly selective effects on associative learning and memory, leaving motor and affective behaviors intact. For instance, NSG2 KO animals performed equivalent to wild-type C57Bl/6n mice on rotarod and Catwalk motor tasks, and did not display alterations in anxiety-like behavior on open field and elevated zero maze tasks. However, NSG2 KO animals demonstrated enhanced recall in the Morris water maze, accelerated reversal learning in a touch-screen task, and accelerated acquisition and enhanced recall on a Trace Fear Conditioning task. Together, these data point to a specific involvement of NSG2 on multiple types of associative learning, and expand the repertoire of pathways that can be targeted for cognitive enhancement.

Fetal alcohol spectrum disorder (FASD) is the most common preventable form of developmental and neurobehavioral disability. Animal models have demonstrated that even low to moderate prenatal alcohol exposure (PAE) is sufficient to impair behavioral flexibility in multiple domains. Previously, utilizing a moderate limited access drinking in the dark paradigm, we have shown that PAE 1) impairs touchscreen pairwise visual reversal in male adult offspring 2) leads to small but significant decreases in orbitofrontal (OFC) firing rates 3) significantly increases dorsal striatum (dS) activity and 4) aberrantly sustains OFC-dS synchrony across early reversal. In the current study, we examined whether optogenetic stimulation of OFC-dS projection neurons would be sufficient to rescue the behavioral inflexibility induced by PAE in male C57BL/6J mice. Following discrimination learning, we targeted OFC-dS projections using a retrograde adeno-associated virus (AAV) delivered to the dS which expressed channel rhodopsin (ChR2). During the first four sessions of reversal learning, we delivered high frequency optogenetic stimulation to the OFC via optic fibers immediately following correct choice responses. Our results show that optogenetic stimulation significantly reduced the number of sessions, incorrect responses, and correction errors required to move past the early perseverative phase for both PAE and control mice. In addition, OFC-dS stimulation during early reversal learning reduced the increased sessions, correct and incorrect responding seen in PAE mice during the later learning phase of reversal but did not significantly alter later performance in control ChR2 mice. Taken together these results suggest that stimulation of OFC-dS projections can improve early reversal learning in PAE and control mice, and these improvements can persist even into later stages of the task days later. These studies provide an important foundation for future clinical approaches to improve executive control in those with FASD. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

BACKGROUND:Prenatal alcohol exposure (PAE) continues to be a worldwide problem. Affected offspring display impaired neurodevelopment, including difficulties with executive control. Although PAE has also been associated with decreased blood flow to fetuses, the relationship between PAE and altered blood flow is not well understood.METHODS:We used preclinical models of PAE, transient systemic hypoxia ischemia (TSHI), and PAE + TSHI combined to assess the effects on neurodevelopmental outcomes using translationally relevant touchscreen operant platform testing. Twenty-eight Long-Evans (Blue Spruce, Strain HsdBlu:LE) dams were randomly assigned to one of four experimental groups: Saccharin Control (Sham), 5% Ethanol (PAE), TSHI, or 5% Ethanol and TSHI (PAE + TSHI). Dams consumed either saccharin or 5% ethanol during gestation. TSHI was induced on Embryonic Day 19 (E19) during an open laparotomy where the uterine arteries were transiently occluded for 1 h. Pups were born normally and, after weaning, were separated by sex. A total of 80 offspring, 40 males and 40 females, were tested on the 5-Choice Continuous Performance paradigm (5C-CPT).RESULTS:Female offspring were significantly impacted by TSHI, but not PAE, with an increase in false alarms and a decrease in hit rates, omissions, accuracy, and correct choice latencies. In contrast, male offspring were mildly affected by PAE, but not TSHI, showing decreases in premature responses and increases in accuracy. No significant interactions between PAE and TSHI were detected on any measure.CONCLUSION:Transient systemic hypoxia ischemia impaired performance on the 5C-CPT in females, leading to a bias toward stimulus responsivity regardless of stimulus type. In contrast, TSHI did not affect male offspring, and only slight effects of PAE were seen. Together, these data suggest that TSHI in females may cause alterations in cortical structures that override alterations caused by moderate PAE.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

CircHomer1 is an activity-dependent circular RNA (circRNA) isoform produced from back-splicing of the Homer1 transcript. Homer1 isoforms are well-known regulators of homeostatic synaptic plasticity through post-synaptic density scaffold regulation. Homer1 polymorphisms have been associated with psychiatric diseases including schizophrenia (SCZ) and bipolar disorder (BD). Postmortem tissue from patients with SCZ and BD displayed reduced circHomer1 levels within the orbitofrontal cortex (OFC), a region that tracks event saliency important for modulating behavioral flexibility. While dysregulation of circHomer1 expression has recently been identified across multiple psychiatric and neurodegenerative disorders and is associated with impaired behavioral flexibility in mice, it is unknown whether circHomer1 can induce electrophysiological signatures relevant to cognitive dysfunction in these disorders. To examine the role of circHomer1 in neuronal signaling, we bilaterally knocked down circHomer1 in the OFC of C57BL/6 J male mice and recorded neural activity from the OFC during a touchscreen reversal learning task then measured molecular changes of synaptic regulators following knockdown. Knockdown of circHomer1 within the OFC induced choice-dependent changes in multiunit firing rate and local field potential coordination and power to salient stimuli during reversal learning. Further, these electrophysiological changes were associated with transcriptional downregulation of glutamatergic signaling effectors and behavioral alterations leading to impaired cognitive flexibility. CircHomer1 is a stable biomolecule, whose knockdown in rodent OFC produces lasting electrophysiological and transcriptional changes important for efficient reversal learning. This is, to our knowledge, the first demonstration of a psychiatric-associated circRNA contributing to electrophysiological, transcriptional, and behavioral alterations relevant to psychiatric phenotypes.

Behavioral flexibility, one of the core executive functions of the brain, has been shown to be an essential skill for survival across species. Corticostriatal circuits play a critical role in mediating behavioral flexibility. The molecular mechanisms underlying these processes are still unclear. Here, we measured how synaptic glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartic acid receptor (NMDAR) expression dynamically changed during specific stages of learning and reversal. Following training to well-established stages of discrimination and reversal learning on a touchscreen visual task, lateral orbitofrontal cortex (OFC), dorsal striatum (dS) as well as medial prefrontal cortex (mPFC), basolateral amygdala (BLA) and piriform cortex (Pir) were micro dissected from male mouse brain and the expression of glutamatergic receptor subunits in the synaptic fraction were measured via immunoblotting. We found that the GluN2B subunit of NMDAR in the OFC remained stable during initial discrimination learning but significantly increased in the synaptic fraction during mid-reversal stages, the period during which the OFC has been shown to play a critical role in updating outcome expectancies. In contrast, both GluA1 and GluA2 subunits of the AMPAR significantly increased in the dS synaptic fraction as new associations were learned late in reversal. Expression of NMDAR and AMPAR subunits did not significantly differ across learning stages in any other brain region. Together, these findings further support the involvement of OFC-dS circuits in moderating well-learned associations and flexible behavior and suggest that dynamic synaptic expression of NMDAR and AMPAR in these circuits may play a role in mediating efficient learning during discrimination and the ability to update previously learned associations as environmental contingencies change.

Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied. Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD + boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions.

Due to increasing advances in their manufacture and functionalization, nanoparticle-based systems have become a popular tool for in vivo drug delivery and biodetection. Recently, scintillating nanoparticles such as yttrium orthosilicate doped with cerium (Y2(SiO4)O:Ce) have come under study for their potential utility in optogenetic applications, as they emit photons upon low levels of stimulation from remote x-ray sources. The utility of such nanoparticles in vivo is hampered by rapid clearance from circulation by the mononuclear phagocytic system, which heavily restricts nanoparticle accumulation at target tissues. Local transcranial injection of nanoparticles may deliver scintillating nanoparticles to highly specific brain regions by circumventing the blood-brain barrier and avoiding phagocytic clearance. Few studies to date have examined the distribution and response to nanoparticles following localized delivery to cerebral cortex, a crucial step in understanding the therapeutic potential of nanoparticle-based biodetection in the brain. Following the synthesis and surface modification of these nanoparticles, two doses (1 and 3 mg/ml) were introduced into mouse secondary motor cortex (M2). This region was chosen as the site for RLP delivery, as it represents a common target for optogenetic manipulations of mouse behavior, and RLPs could eventually serve as an injectable x-ray inducible light delivery system. The spread of particles through the target tissue was assessed 24 hours, 72 hours, and 9 days post-injection. Y2(SiO4)O:Ce nanoparticles were found to be detectable in the brain for up to 9 days, initially diffusing through the tissue until 72 hours before achieving partial clearance by the final endpoint. Small transient increases in the presence of IBA-1+ microglia and GFAP+ astrocytic cell populations were detected near nanoparticle injection sites of both doses tested 24 hours after surgery. Taken together, these data provide evidence that Y2(SiO4)O:Ce nanoparticles coated with BSA can be injected directly into mouse cortex in vivo, where they persist for days and are broadly tolerated, such that they may be potentially utilized for remote x-ray activated stimulation and photon emission for optogenetic experiments in the near future.

Background: Fetal alcohol spectrum disorders (FASDs) are characterized by a wide range of physical, cognitive, and behavioral impairments that occur throughout the lifespan. Prenatal alcohol exposure (PAE) can lead to adult impairments in cognitive control behaviors mediated by the posterior parietal cortex (PPC). The PPC plays a fundamental role in the performance of response tasks in both primates and rodents, specifically when choices between similar target and nontarget stimuli are required. Furthermore, the PPC is reciprocally connected with other cortical areas. Despite the extensive literature investigating the molecular mechanisms underlying PAE impairments in cognitive functions mediated by cortical areas, little is known regarding the long-term effects of PAE on PPC development and function. Here, we examined changes in the cellular organization of GABAergic interneurons and their function in PPC using behaviorally naive control and PAE mice.Methods: We used a limited access model of PAE in which C57BL/6J females were exposed to a solution of 10% (w/v) ethanol and 0.066% (w/V) saccharin for 4 h/day throughout gestation. Using high-throughput fluorescent microscopy, we quantified the levels of GABAergic interneurons in the PPC of adult PAE and control offspring. In a separate cohort, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch clamp recordings from PPC layer 5 pyramidal neurons.Results: PAE led to a significant overall reduction of parvalbumin-expressing GABAergic interneurons in PAE mice regardless of sex. Somatostatin- and calretinin-expressing GABAergic interneurons were not affected. Interestingly, PAE did not modulate sIPSC amplitude or frequency.Conclusions: These results suggest that impairments in cognitive control observed in FASD may be due to the significant reduction of parvalbumin-expressing GABAergic interneurons in the PPC. PAE animals may show compensatory changes in GABAergic function following developmental reduction of these interneurons.

Reduced willingness to engage in effort is a hallmark of anhedonia. Quantifying willingness to expend effort is critical in determining underlying neural mechanisms and developing targeted therapeutics, but cross-species neural biomarkers are lacking. We used a reverse-translated cognitive effort task (CET) during electroencephalographic (EEG) recording to: (1) identify neurophysiological correlates of effortful decision-making; and (2) compare biomarkers across participants who prefer easy versus hard trials.

Fetal alcohol spectrum disorders (FASDs) are characterized by a wide range of physical, cognitive, and behavioral impairments that occur throughout the lifespan. Prenatal alcohol exposure (PAE) can lead to adult impairments in cognitive control behaviors mediated by the posterior parietal cortex (PPC). The PPC plays a fundamental role in the performance of response tasks in both primates and rodents, specifically when choices between similar target and nontarget stimuli are required. Furthermore, the PPC is reciprocally connected with other cortical areas. Despite the extensive literature investigating the molecular mechanisms underlying PAE impairments in cognitive functions mediated by cortical areas, little is known regarding the long-term effects of PAE on PPC development and function. Here, we examined changes in the cellular organization of GABAergic interneurons and their function in PPC using behaviorally naïve control and PAE mice. We used a limited access model of PAE in which C57BL/6J females were exposed to a solution of 10% (w/v) ethanol and 0.066% (w/V) saccharin for 4 h/day throughout gestation. Using high-throughput fluorescent microscopy, we quantified the levels of GABAergic interneurons in the PPC of adult PAE and control offspring. In a separate cohort, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch clamp recordings from PPC layer 5 pyramidal neurons. PAE led to a significant overall reduction of parvalbumin-expressing GABAergic interneurons in PAE mice regardless of sex. Somatostatin- and calretinin-expressing GABAergic interneurons were not affected. Interestingly, PAE did not modulate sIPSC amplitude or frequency. These results suggest that impairments in cognitive control observed in FASD may be due to the significant reduction of parvalbumin-expressing GABAergic interneurons in the PPC. PAE animals may show compensatory changes in GABAergic function following developmental reduction of these interneurons.

Circular RNAs (circRNAs) are a novel category of non-coding RNAs derived from the back-splicing and covalent joining of exons or introns. Recent studies have suggested that circRNAs are preferentially generated from synaptic plasticity-related genes and are particularly enriched in the brain. Although some circRNAs have been found to sequester microRNAs and others to associate with RNA-binding proteins (RBPs), the mechanism of action of most circRNAs remains poorly understood. Moreover, little is known about the potential involvement of circRNAs in Alzheimer’s disease (AD).

IntroductionFetal Alcohol Spectrum Disorders (FASD) are the leading cause of preventable developmental disability and are commonly characterized by alterations in executive function. Reversal learning tasks are reliable, cross-species methods for testing a frequently impaired aspect of executive control, behavioral flexibility. Pre-clinical studies commonly require the use of reinforcers to motivate animals to learn and perform the task. While there are several reinforcers available, the most commonly employed are solid (food pellets) and liquid (sweetened milk) rewards. Previous studies have examined the effects of different solid rewards or liquid dietary content on learning in instrumental responding and found that rodents on liquid reward with higher caloric content performed better with increased response and task acquisition rate. The influence of reinforcer type on reversal learning and how this interacts with developmental insults such as prenatal alcohol exposure (PAE) has not been explored. MethodsWe tested whether reinforcer type during learning or reversal would impact an established deficit in PAE mice. ResultsWe found that all male and female mice on liquid reward, regardless of prenatal exposure were better motivated to learn task behaviors during pre-training. Consistent with previous findings, both male and female PAE mice and Saccharine control mice were able to learn the initial stimulus reward associations irrespective of the reinforcer type. During the initial reversal phase, male PAE mice that received pellet rewards exhibited maladaptive perseverative responding whereas male mice that received liquid rewards performed comparable to their control counterparts. Female PAE mice that received either reinforcer types did not exhibit any deficits on behavioral flexibility. Female saccharine control mice that received liquid, but not pellet, rewards showed increased perseverative responding during the early reversal phase. DiscussionThese data suggest that reinforcer type can have a major impact on motivation, and therefore performance, during reversal learning. Highly motivating rewards may mask behavioral deficits seen with more moderately sought rewards and gestational exposure to the non-caloric sweetener, saccharine, can impact behavior motivated by those reinforcers in a sex-dependent manner.

We recently advanced a rodent homologue for the reward-specific, event-related potential component observed in humans known as the Reward Positivity. We sought to determine the cortical source of this signal in mice to further test the nature of this homology. While similar reward-related cortical signals have been identified in rats, these recordings were all performed in cingulate gyrus. Given the value-dependent nature of this event, we hypothesized that more ventral prelimbic and infralimbic areas also contribute important variance to this signal. Depth probes assessed local field activity in 29 mice (15 males) while they completed multiple sessions of a probabilistic reinforcement learning task. Using a priori regions of interest, we demonstrated that the depth of recording in the cortical midline significantly correlated with the size of reward-evoked delta band spectral activity as well as the single trial correlation between delta power and reward prediction error. These findings provide important verification of the validity of this translational biomarker of reward responsiveness, learning, and valuation.

Although it is well established that alcohol consumption during pregnancy can lead to lifelong difficulties in offspring, Fetal Alcohol Spectrum Disorders (FASD) remain a common neurodevelopmental syndrome. Translational behavioral tools that target similar brain circuits across species can facilitate understanding of these cognitive consequences. Touchscreen behavioral tasks for rodents enable easy integration of dura recordings of electroencephalographic (EEG) activity in awake behaving animals, with clear translational generalizability. Recently, we showed that Prenatal Alcohol Exposure (PAE) impairs cognitive control on the touchscreen 5Choice Continuous Performance Task (5C-CPT) which requires animals to touch on target trials (hit) and withhold responding on non-target trials (correct rejection). Here, we extended these findings to determine whether dura EEG recordings would detect task-relevant differences in medial prefrontal cortex (mPFC) and posterior parietal cortex (PPC) corresponding with behavioral alterations in PAE animals. Replicating previous findings, PAE mice made more false alarm responses versus controls and had a significantly lower sensitivity index. All mice, regardless of sex or treatment, demonstrated increased frontal theta-band power during correct trials that followed an error (similar to post-error monitoring commonly seen in human participants). All mice showed a significant decrease in parietal beta-band power when performing a correct rejection versus a hit. PAE mice of both sexes showed a significantly larger decrease in parietal beta-band power when successfully rejecting non-target stimuli. These findings suggest that moderate exposure to alcohol during development can have long lasting effects on cognitive control, and task-relevant neural signals may provide a biomarker of impaired function across species.