Sex-specific alterations in cognitive control following moderate prenatal alcohol exposure and transient systemic hypoxia ischemia in the rat.

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.

Optogenetic stimulation of corticostriatal circuits improves behavioral flexibility in mice with prenatal alcohol exposure.

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".

Dynamic regulation of corticostriatal glutamatergic synaptic expression during reversal learning in male mice.

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.

Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

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.

Long-term effects of low prenatal alcohol exposure on GABAergic interneurons of the murine posterior parietal cortex.

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 naïve 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.

Aging, longevity, and the role of environmental stressors: a focus on wildfire smoke and air quality.

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.

Depth recordings of the mouse homologue of the Reward Positivity.

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.

Proceedings of the 2022 annual meeting of the Fetal Alcohol Spectrum Disorders study group.

The 2022 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was held in coordination with the 45th annual Research Society on Alcoholism conference on June 25th, 2022. The theme of the meeting was "Enhancing the Relevance of Research for the Community." The program began with a moderated panel discussion on the value of community-engaged research, which included two self-advocates and a clinical and pre-clinical researcher. Invited plenary speakers included Jill Locke, Ph.D., who provided an engaging introduction to implementation science, and Jared Young, Ph.D., who discussed cross-species domain task specificity. The meeting also included updates from three government agencies, short presentations by junior and senior investigators showcasing late-breaking FASD research, trainee award winners, and a presentation on the Toward Health Outcomes intervention roadmap by Jacqueline Pei, Ph.D.

Reinforcer value moderates the effects of prenatal alcohol exposure on learning and reversal.

Introduction: Fetal 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. Methods: We tested whether reinforcer type during learning or reversal would impact an established deficit in PAE mice. Results: We 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. Discussion: These 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.

Impaired cognitive control after moderate prenatal alcohol exposure corresponds to altered EEG power during a rodent touchscreen continuous performance task.

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 5-Choice 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.

Distribution and inflammatory cell response to intracranial delivery of radioluminescent Y2(SiO4)O:Ce particles.

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.

KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization.

The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of mRNAs with AU-rich elements. KHSRP was previously shown to destabilize Gap43 mRNA and decrease neurite growth in cultured embryonic neurons. Here, we have tested functions of KHSRP in vivo. We find upregulation of 1460 mRNAs in neocortex of adult Khsrp-/- mice, of which 527 bind to KHSRP with high specificity. These KHSRP targets are involved in pathways for neuronal morphology, axon guidance, neurotransmission and long-term memory. Khsrp-/- mice show increased axon growth and dendritic spine density in vivo. Neuronal cultures from Khsrp-/- mice show increased axon and dendrite growth and elevated KHSRP-target mRNAs, including subcellularly localized mRNAs. Furthermore, neuron-specific knockout of Khsrp confirms these are from neuron-intrinsic roles of KHSRP. Consistent with this, neurons in the hippocampus and infralimbic cortex of Khsrp-/- mice show elevations in frequency of miniature excitatory postsynaptic currents. The Khsrp-/- mice have deficits in trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, these results indicate that deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.

Amphetamine alters an EEG marker of reward processing in humans and mice.

The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.

EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants.

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week. D-amp boosted d-prime, sped reaction time, and increased frontal P3a amplitude to non-target correct rejections independent of task difficulty. Task difficulty did however, moderate d-amp effects on EEG during target performance. D-amp suppressed frontal theta power during easy target responses which negatively correlated with drug-induced improvement in hit rate while d-amp-induced changes in P3b amplitude during hard target trials strongly correlated with drug-induced improvement in hit rate. In summary, d-amp affected both behavioral and neurophysiological measures of cognitive control elements. Under low-demand, d-amp diminished cognitive control by suppressing theta, yet under high-demand it boosted control in concert with higher P3b amplitudes. These findings thus appear to reflect a gain-sharpening effect of d-amp: during high-demand processes were boosted while during low-demand processes were neglected. Future studies will use these neurophysiological measures of cognitive control as biomarkers to predict d-amp sensitivity in people with cognitive control deficits, including schizophrenia.

A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning.

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b-specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease.

Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency.

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Impaired cognitive flexibility following NMDAR-GluN2B deletion is associated with altered orbitofrontal-striatal function.

A common feature across neuropsychiatric disorders is inability to discontinue an action or thought once it has become detrimental. Reversal learning, a hallmark of executive control, requires plasticity within cortical, striatal and limbic circuits and is highly sensitive to disruption of N-methyl-d-aspartate receptor (NMDAR) function. In particular, selective deletion or antagonism of GluN2B containing NMDARs in cortical regions including the orbitofrontal cortex (OFC), promotes maladaptive perseveration. It remains unknown whether GluN2B functions to maintain local cortical activity necessary for reversal learning, or if it exerts a broader influence on the integration of neural activity across cortical and subcortical systems. To address this question, we utilized in vivo electrophysiology to record neuronal activity and local field potentials (LFP) in the orbitofrontal cortex and dorsal striatum (dS) of mice with deletion of GluN2B in neocortical and hippocampal principal cells while they performed touchscreen reversal learning. Reversal impairment produced by corticohippocampal GluN2B deletion was paralleled by an aberrant increase in functional connectivity between the OFC and dS. These alterations in coordination were associated with alterations in local OFC and dS firing activity. These data demonstrate highly dynamic patterns of cortical and striatal activity concomitant with reversal learning, and reveal GluN2B as a molecular mechanism underpinning the timing of these processes.

Sex-specific effect of prenatal alcohol exposure on N-methyl-D-aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice.

BACKGROUND: Alcohol consumption during pregnancy can produce behavioral and cognitive deficits that persist into adulthood. These include impairments in executive functions, learning, planning, and cognitive flexibility. We have previously shown that moderate prenatal alcohol exposure (PAE) significantly impairs reversal learning, a measure of flexibility mediated across species by different brain areas that include the orbital frontal cortex (OFC). Reversal learning is likewise impaired by genetic or pharmacological inactivation of GluN2B subunit-containing N-methyl-D-aspartate receptors (NMDARs). In the current study, we tested the hypothesis that moderate PAE persistently alters the number and function of GluN2B subunit-containing NMDARs in OFC pyramidal neurons of adult mice. METHODS: We used a rodent model of fetal alcohol spectrum disorders and left offspring undisturbed until adulthood. Using whole-cell, patch-clamp recordings, we assessed NMDAR function in slices from 90- to 100-day-old male and female PAE and control mice. Pharmacologically isolated NMDA receptor-mediated evoked excitatory postsynaptic currents (NMDA-eEPSCs) were recorded in the absence and presence of the GluN2B antagonist, Ro25-6981(1 µM). In a subset of littermates, we evaluated the level of GluN2B protein expression in the synaptic fraction using Western blotting technique. RESULTS: Our results indicate that PAE females show significantly larger (~23%) NMDA-eEPSC amplitudes than controls, while PAE induced a significant decrease (~17%) in NMDA-eEPSC current density of pyramidal neurons recorded in slices from male mice. NMDA-eEPSC decay time was not affected in PAE-exposed mice from either sex. The contribution of GluN2B subunit-containing NMDARs to the eEPSCs was not significantly altered by PAE. Moreover, there were no significant changes in protein expression in the synaptic fraction of either PAE males or females. CONCLUSIONS: These findings suggest that low-to-moderate PAE modulates NMDAR function in pyramidal neurons in a sex-specific manner, although we did not find evidence that the effect is mediated by dysfunction of synaptic GluN2B subunit-containing NMDARs.

Electrophysiological biomarkers of behavioral dimensions from cross-species paradigms.

There has been a fundamental failure to translate preclinically supported research into clinically efficacious treatments for psychiatric disorders. One of the greatest impediments toward improving this species gap has been the difficulty of identifying translatable neurophysiological signals that are related to specific behavioral constructs. Here, we present evidence from three paradigms that were completed by humans and mice using analogous procedures, with each task eliciting candidate a priori defined electrophysiological signals underlying effortful motivation, reinforcement learning, and cognitive control. The effortful motivation was assessed using a progressive ratio breakpoint task, yielding a similar decrease in alpha-band activity over time in both species. Reinforcement learning was assessed via feedback in a probabilistic learning task with delta power significantly modulated by reward surprise in both species. Additionally, cognitive control was assessed in the five-choice continuous performance task, yielding response-locked theta power seen across species, and modulated by difficulty in humans. Together, these successes, and also the teachings from these failures, provide a roadmap towards the use of electrophysiology as a method for translating findings from the preclinical assays to the clinical settings.