Cannabis use during 2021pregnancy is common as many pregnant women consider cannabis as a safe way to alleviate symptoms associated with pregnancy because it is “natural”. However, clinical evidence links perinatal cannabis exposure to externalizing behavior in offspring. In preclinical research, most studies focus on exposure to the psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC). THC is lipophilic, allowing it to cross the placental barrier and be secreted in maternal milk, thereby exposing the fetus/neonate. We used operant procedures to measure motivation and impulsivity in adult offspring perinatally exposed to THC. Dams were orally exposed to 0 or 5 mg/kg/day THC daily from 14 days prior to breeding to postnatal day (PND) 14. Differential reinforcement of high rates (DRH) and differential reinforcement of low rates (DRL) of responding tasks were used to examine motivation and impulsive action. We also measured dopamine (DA) functioning in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) via in vivo fixed potential amperometry in littermates of rats that completed behavioral testing. Perinatal THC exposure had minimal effects on impulsive action measures during DRL 15s. Rather, perinatal THC exposure decreased DRL 15s burst responses and completed trials in both sexes, and reinforcers earned in THC-exposed males. Decreased lever presses during DRH were observed in both sexes perinatally exposed to THC, as well as fewer reinforcers in THC-exposed males. THC exposure did not alter baseline DA release in the NAc or mPFC, but did attenuate the dopaminergic response to cocaine in the NAc. These results suggest perinatal exposure to THC can decrease motivation to work for reinforcers during high-effort tasks, that this effect may be more pronounced in males, and that the “amotivational state” resulting from perinatal THC exposure may be due to reinforcer devaluation. Keywords: oral THC, developmental neurotoxicology, amotivational syndrome, mesocorticolimbic dopamine.

BACKGROUND/OBJECTIVES:Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, impulsivity, and hyperactivity. However, inattention remains unexplored. METHODS:We assessed automatic attention in Lphn3 KO (n = 19) and their control line (wildtype/WT, n = 20) through use of the following auditory event-related potentials (ERPs): P1, N1, P2, and N2. We also extended this exploratory study by comparing these same ERPs in spontaneously hypertensive rats (SHRs, n = 16), the most commonly studied animal model of ADHD, to their control line (Wistar-Kyoto/WKY, n = 20). Electroencephalograms (EEG) were recorded using subdermal needle electrodes at frontocentral sites while freely moving rats were presented with five-tone trains (50 ms tones, 400 ms tone onset asynchronies) with varying short (1 s) and long (5 s) inter-train intervals. Peak amplitudes and latencies were analyzed using GLM-mixed ANOVAs to assess differences across genotypes (KO vs. WTs) and strains (SHRs vs. WKYs). RESULTS:The KOs did not demonstrate any significant differences in peak amplitudes relative to the WT controls, suggesting that the null expression of Lphn3 does not result in the development of inefficiencies in automatic attention. However, the SHRs exhibited significantly reduced peak P1 (and peak-to-peak P1-N1) values relative to the WKYs. These attenuations likely reflect inefficiencies in bottom-up arousal networks that are necessary for efficient automatic processing. CONCLUSIONS:Distinct findings between these animal models likely reflect differing alterations in dopamine and noradrenaline neurotransmission that may underlie ADHD-relevant phenotypes.

We examined DA activity in the medial prefrontal cortex (mPFC) and nucleus accumbens core (NAcc) in two Different Rat Models of Attention-Deficit/Hyperactivity Disorder: Spontaneously Hypertensive Rats (SHR) Versus Lphn3 Knockout Rats. We examined baseline stimulation-evoked phasic DA release, half-life, and DA autoreceptor (DAR) functioning in the mPFC and NAcc, as well as the response to nomifensine (10 mg/kg, IP), a DA transporter (DAT) blocker, on these measures in the NAcc. Both rat models were hypodopaminergic, with notable regional and mechanistic differences. The SHRs displayed decreased DA release in the NAcc compared to their control strain (i.e., WKY rats), with no differences in the mPFC, leading a much lower NAcc-to-PFC DA release ratio in SHRs compared to controls suggesting an imbalance in DA transmission between these regions. The Lphn3 KO rats were considered hypodopaminergic based on the reduced summed DA release in the mPFC and NAcc compared to WT controls, although differences were not observed when examining each site independently. Lphn3 KOs displayed increased DA half-life in the mPFC compared with Lphn3 WT rats, an indication of decreased DAT reuptake, with no differences in the NAcc. DAT blockade by nomifensine had a similar effect on DA release in the NAcc of SHRs and WKYs, but increased DA release in the NAcc of Lphn3 KOs to a greater extent than in WTs. These results suggest that the efficacy of pharmacotherapies used to treat externalizing disorders such as ADHD and/or SUD, likely differ between SHRs and Lphn3 KO rats.

With grant support from the Research Experience for Undergraduates (REU) program funded by the National Science Foundation (NSF) and the Awards to Stimulate and Support Undergraduate Research Experiences (ASSURE) program funded by the Department of Defense (DoD) Air Force Office of Scientific Research (AFOSR), we established a program intended to increase the number of underrepresented racial and ethnic minority (URM) and first-generation undergraduate students successfully applying to neuroscience and other STEM-related graduate programs. The Neuroscience Techniques and Research Training (NeuroSTART) Program aimed to increase the number of undergraduate students from the Memphis area involved in behavioral neuroscience research. In this two-semester program, students completed an empirical research project in a neuroscience lab, received individual mentoring from neuroscience faculty, became part of a STEM network, presented at research conferences, and attended specialized professional development seminars. In two cohorts of 15 students, 4 are PhD students in neuroscience-related programs or in medical school (27%), 4 are employed in neuroscience-related research facilities (27%), 3 are employed as clinical assistants (20%), and 1 is employed in the IT field (7%). The remaining three recently graduated and are planning a gap year prior to applying for admission to grad/medical school. The Memphis NeuroSTART program has provided valuable training to participants, making them competitive applicants for jobs in the health sciences and for admittance into graduate neuroscience programs. By providing this training to first-generation and URM students, the broader impact of this program was an increase in the diversity of the health sciences workforce, particularly those specializing in neuroscience-related research and treatment.

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N -arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase (FAAH) inhibition while also inhibiting transient receptor potential vanilloid type 1 (TRPV1) channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor type 1 (CB1R) agonist arachidonoyl-2’-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with 7 daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA did not alter locomotor activity but did decrease phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference (CPP) then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a CPP or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct CB 1 R agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism.

Exposure to combinations of environmental toxins is growing in prevalence; and therefore, understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins, polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise, interact to produce dysfunction in central auditory processing. PCBs are well established to impose negative developmental impacts on hearing. However, it is not known whether developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 min of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma.In vivotwo-photon imaging of the inferior colliculus (IC) revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins.SIGNIFICANCE STATEMENTExposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the prenatal and postnatal developmental changes induced by polychlorinated biphenyls (PCBs) could negatively impact the resilience of the brain to noise-induced hearing loss (NIHL) later in adulthood. The use of state-of-the-art tools, includingin vivomultiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.

IntroductionImpulsivity is a symptom of attention-deficit/hyperactivity disorder (ADHD) and variants in the Lphn3 (Adgrl3) gene (OMIM 616417) have been linked to ADHD. This project utilized a delay-discounting (DD) task to examine the impact of Lphn3 deletion in rats on impulsive choice. “Positive control” measures were also collected in spontaneously hypertensive rats (SHRs), another animal model of ADHD.MethodsFor Experiment I, rats were given the option to press one lever for a delayed reward of 3 food pellets or the other lever for an immediate reward of 1 pellet. Impulsive choice was measured as the tendency to discount the larger, delayed reward. We hypothesized that impulsive choice would be greater in the SHR and Lphn3 knockout (KO) rats relative to their control strains - Wistar-Kyoto (WKY) and Lphn3 wildtype (WT) rats, respectively.ResultsThe results did not completely support the hypothesis, as only the SHRs (but not the Lphn3 KO rats) demonstrated a decrease in the percent choice for the larger reward. Because subsequent trials did not begin until the end of the delay period regardless of which lever was selected, rats were required to wait for the next trial to start even if they picked the immediate lever. Experiment II examined whether the rate of reinforcement influenced impulsive choice by using a DD task that incorporated a 1 s inter-trial interval (ITI) immediately after delivery of either the immediate (1 pellet) or delayed (3 pellet) reinforcer. The results of Experiment II found no difference in the percent choice for the larger reward between Lphn3 KO and WT rats, demonstrating reinforcement rate did not influence impulsive choice in Lphn3 KO rats.DiscussionOverall, there were impulsivity differences among the ADHD models, as SHRs exhibited deficits in impulsive choice, while the Lphn3 KO rats did not.

Attention-deficit/hyperactivity disorder (ADHD) a common neurodevelopmental disorder of childhood and often comorbid with other externalizing disorders (EDs). There is evidence that externalizing behaviors share a common genetic etiology. Recently, a genome-wide, multigenerational sample linked variants in the Lphn3 gene to ADHD and other externalizing behaviors. Likewise, limited research in animal models has provided converging evidence that Lphn3 plays a role in EDs. This study examined the impact of Lphn3 deletion (i.e., Lphn3-/- ) in rats on measures of behavioral control associated with externalizing behavior. Impulsivity was assessed for 30 days via a differential reinforcement of low rates (DRL) task and working memory evaluated for 25 days using a delayed spatial alternation (DSA) task. Data from both tasks were averaged into 5-day testing blocks. We analyzed overall performance, as well as response patterns in just the first and last blocks to assess acquisition and steady-state performance, respectively. "Positive control" measures on the same tasks were measured in an accepted animal model of ADHD-the spontaneously hypertensive rat (SHR). Compared with wildtype controls, Lphn3-/- rats exhibited deficits on both the DRL and DSA tasks, indicative of deficits in impulsive action and working memory, respectively. These deficits were less severe than those in the SHRs, who were profoundly impaired on both tasks compared with their control strain, Wistar-Kyoto rats. The results provide evidence supporting a role for Lphn3 in modulating inhibitory control and working memory, and suggest additional research evaluating the role of Lphn3 in the manifestation of EDs more broadly is warranted.

Long-latency auditory evoked potentials (LLAEPs) may help further advances in understanding consciousness under general anesthesia and promote more objective means of assessing sedation depth than conventional clinical signs. Among the LLAEP components, the auditory N1 shows promise as a measure of sedation depth and a marker of consciousness, but findings are so far inconclusive. Research with animals can help elucidate the effects of various anesthetics on the N1 and other LLAEPs, but investigations of LLAEPs under anesthesia in animals is lacking. To address this deficit, we examined the P1, N1, P2, and N2, along with their corresponding peak-to-peak complexes, in 10 Wistar rats anesthetized with 1.5-2 % isoflurane in pure oxygen and again after recovery. While under anesthesia, subdermal needle electrodes were inserted and secured for electroencephalographic (EEG) recordings. LLAEPs were assessed during a 20-min, passive, two-tone (500 ms inter-tone interval) paradigm with randomized short (1 s) and long (5 s) inter-pair intervals (IPIs). Overall, while the LLAEP peaks under isoflurane were less defined, they were not eliminated. The peak-to-peak amplitudes, particularly the P1-N1, were significantly smaller under isoflurane than during post-recovery. Our preliminary findings indicate that isoflurane produces global suppression across LLAEP components, presumably reflecting impaired integration of top-down and bottom-up attention and sensory systems under profound sedation with isoflurane.

Objectives Mounting evidence suggests diet and exercise influence learning and memory (LM). We compared a high-fat, high-sucrose Western diet (WD) to a plant-based, amylose/amylopectin blend, lower-fat diet known as the Daniel Fast (DF) in rats with and without regular aerobic exercise on a task of spatial working memory (WM). Methods Rats were randomly assigned to the WD or DF at 6 weeks of age. Exercised rats (WD-E, DF-E) ran on a treadmill 3 times/week for 30 min while the sedentary rats did not (WD-S, DF-S). Rats adhered to these assignments for 12 weeks, inclusive of ab libitum food intake, after which mild food restriction was implemented to encourage responding during WM testing. For nine months, WM performance was assessed once daily, six days per week, after which hippocampal sections were collected for subsequent analysis of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal protein (ARC), and signal transducer and activator of transcription 3 (P-STAT3, Tyr705). Results DF-E rats exhibited the best DSA performance. Surprisingly, the WD-S group outperformed the WD-E group, but had significantly lower BDNF and ARC relative to the DF-S group, with a similar trend from the WD-E group. P-STAT3 expression was also significantly elevated in the WD-S group compared to both the DF-S and WD-E groups. Discussion These results support previous research demonstrating negative effects of the WD on spatial LM, demonstrate the plant-based DF regimen combined with chronic aerobic exercise produces measurable WM and neuroprotective benefits, and suggest the need to carefully design exercise prescriptions to avoid over-stressing individuals making concurrent dietary changes.

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed potential amperometry with carbon fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.

Birth Defects ResearchVolume 111, Issue 9 p. 405-564 59th Annual Teratology Society MeetingFree Access 59th Annual Teratology Society Meeting First published: 13 May 2019 https://doi.org/10.1002/bdr2.1515AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume111, Issue9Special Issue: 59th Annual Teratology Society MeetingMay 15, 2019Pages 405-564 RelatedInformation