Long-term effects of Preweaning environmental impoverishment on neurobehavioral and neurocognitive outcomes in Sprague Dawley rats: An early environmental stress model.

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES conditions often experience more stress than those in other SES groups. There are multiple model systems of early environmental stress (EES), one of which is reduced cage bedding.

Tests for learning and memory in rodent regulatory studies.

For decades, regulatory guidelines for safety assessment in rodents for drugs, chemicals, pesticides, and food additives with developmental neurotoxic potential have recommended a single test of learning and memory (L&M). In recent years some agencies have requested two such tests. Given the importance of higher cognitive function to health, and the fact that different types of L&M are mediated by different brain regions assessing higher functions represents a step forward in providing better evidence-based protection against adverse brain effects.

A Gad2 specific Slc6a8 deletion recapitulates the contextual and cued freezing deficits seen in Slc6a8 mice.

The creatine (Cr)-phosphocreatine shuttle is essential for ATP homeostasis. In humans, the absence of brain Cr causes significant intellectual disability, epilepsy, and language delay. Mutations of the creatine transporter (SLC6A8) are the most common cause of Cr deficiency.

Impulsive choice in two different rat models of ADHD-Spontaneously hypertensive and knockout rats.

Introduction: Impulsivity is a symptom of attention-deficit/hyperactivity disorder (ADHD) and variants in the ) gene (OMIM 616417) have been linked to ADHD. This project utilized a delay-discounting (DD) task to examine the impact of deletion in rats on impulsive choice. "Positive control" measures were also collected in spontaneously hypertensive rats (SHRs), another animal model of ADHD.

Developmental deltamethrin: Sex-specific hippocampal effects in Sprague Dawley rats.

Pyrethroid pesticides are widely used and can cause long-term effects after early exposure. Epidemiological and animal studies reveal associations between pyrethroid exposure and altered cognition following prenatal and/or neonatal exposure. However, little is known about the cellular effects of such exposure.

Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model.

Recent studies suggest that ultra-high dose rates of proton radiation (>40 Gy/s; FLASH) confer less toxicity to exposed healthy tissue and reduce cognitive decline compared with conventional radiation dose rates (~1 Gy/s), but further preclinical data are required to demonstrate this sparing effect. In this study, postnatal day 11 (P11) rats were treated with whole brain irradiation with protons at a total dose of 0, 5, or 8 Gy, comparing a conventional dose rate of 1 Gy/s vs. a FLASH dose rate of 100 Gy/s.

Comprehensive Behavioral Analysis of Opsin 3 (Encephalopsin)-Deficient Mice Identifies Role in Modulation of Acoustic Startle Reflex.

Opsin-3 (, encephalopsin) was the first nonvisual opsin gene discovered in mammals. Since then, several functions have been described, and in two cases (adipose tissue, smooth muscle) light sensing activity is implicated. In addition to peripheral tissues, is robustly expressed within the central nervous system, for which it derives its name.

Latrophilin-3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity.

Latrophilin-3 (LPHN3) is a brain specific G-protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3 variants are associated with some cases of ADHD. Lphn3 KO rats are hyperactive with an attenuated response to ADHD medication and have cognitive deficits.

Translating Neurobehavioral Toxicity Across Species From Zebrafish to Rats to Humans: Implications for Risk Assessment.

There is a spectrum of approaches to neurotoxicological science from high-throughput cell-based assays, through a variety of experimental animal models to human epidemiological and clinical studies. Each level of analysis has its own advantages and limitations. Experimental animal models give essential information for neurobehavioral toxicology, providing cause-and-effect information regarding risks of neurobehavioral dysfunction caused by toxicant exposure.

Neurobehavioral abnormalities following prenatal psychosocial stress are differentially modulated by maternal environment.

Prenatal stress (PS) is associated with increased vulnerability to affective disorders. Transplacental glucocorticoid passage and stress-induced maternal environment alterations are recognized as potential routes of transmission that can fundamentally alter neurodevelopment. However, molecular mechanisms underlying aberrant emotional outcomes or the individual contributions intrauterine stress versus maternal environment play in shaping these mechanisms remain unknown.

Review of rodent models of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a polygenic neurodevelopmental disorder that affects 8-12 % of children and >4 % of adults. Environmental factors are believed to interact with genetic predispositions to increase susceptibility to ADHD. No existing rodent model captures all aspects of ADHD, but several show promise.

An assessment of executive function in two different rat models of attention-deficit hyperactivity disorder: Spontaneously hypertensive versus Lphn3 knockout rats.

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.

A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats.

Latrophilins (LPHNs) are adhesion G protein-coupled receptors with three isoforms but only LPHN3 is brain specific (caudate, prefrontal cortex, dentate, amygdala, and cerebellum). Variants of LPHN3 are associated with ADHD. Null mutations of Lphn3 in rat, mouse, zebrafish, and Drosophila result in hyperactivity, but its role in learning and memory (L&M) is largely unknown.

Issues in the design, analysis, and application of rodent developmental neurotoxicology studies.

Developmental neurotoxicity (DNT) studies could benefit from revisions to study design, data analysis, and some behavioral test methods to enhance reproducibility. The Environmental Protection Agency (EPA) reviewed 69 studies submitted to the Office of Pesticide Programs. Two of the behavioral tests identified the lowest observable adverse effect level (LOAEL) 20 and 13 times, respectively, while the other two tests identified the LOAEL only 3 and 4 times, respectively.

Latrophilin-3 disruption: Effects on brain and behavior.

Latrophilin-3 (LPHN3), a G-protein-coupled receptor belonging to the adhesion subfamily, is a regulator of synaptic function and maintenance in brain regions that mediate locomotor activity, attention, and memory for location and path. Variants of LPHN3 are associated with increased risk for attention deficit hyperactivity disorder (ADHD) in some patients. Here we review the role of LPHN3 in the central nervous system (CNS).

Effects of pyrethroids on brain development and behavior: Deltamethrin.

Deltamethrin (DLM) is a Type II pyrethroid pesticide widely used in agriculture, homes, public spaces, and medicine. Epidemiological studies report that increased pyrethroid exposure during development is associated with neurobehavioral disorders. This raises concern about the safety of these chemicals for children.

Effects of Permethrin or Deltamethrin Exposure in Adult Sprague Dawley Rats on Acoustic and Light Prepulse Inhibition of Acoustic or Tactile Startle.

The effects of permethrin (PRM) and deltamethrin (DLM) on acoustic or light prepulse inhibition of the acoustic startle response (ASR) and tactile startle response (TSR) were studied in adult male Sprague Dawley rats. Preliminary studies were conducted to optimize the parameters of light and acoustic prepulse inhibition of ASR and TSR. Once these parameters were set, a new group of rats was administered PRM (0 or 90 mg/kg) or DLM (0 or 25 mg/kg) by gavage in 5 mL/kg corn oil.

Impact of preweaning stress on long-term neurobehavioral outcomes in Sprague-Dawley rats: Differential effects of barren cage rearing, pup isolation, and the combination.

Two developmental stressors were compared in preweaning rats exposed to either one stressor or both. Stressors were barren cage rearing or maternal separation (pup isolation). 40 gravid Sprague-Dawley CD/IGS rats were randomly assigned to two cage conditions: standard (Std) cage or barren cage (Bar), 20 litters/condition throughout gestation and lactation.

Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects.

Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes.

The potassium channel Kv4.2 regulates dendritic spine morphology, electroencephalographic characteristics and seizure susceptibility in mice.

The voltage-gated potassium channel Kv4.2 is a critical regulator of dendritic excitability in the hippocampus and is crucial for dendritic signal integration. Kv4.

This is your teen brain on drugs: In search of biological factors unique to dependence toxicity in adolescence.

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence.

Enhanced Transient Striatal Dopamine Release and Reuptake in Knockout Rats.

Latrophilin-3 (LPHN3) is an adhesion G protein coupled receptor involved in regulating neuroplasticity. Variants of are associated with increased risk of attention-deficit hyperactivity disorder. Data from mouse, zebrafish, , and rat show that disruption of LPHN3 results in hyperactivity, and in the Sprague-Dawley knockout rat, exhibit deficits in learning and memory and changes in dopamine (DA) markers in the neostriatum.

Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression.

Postpartum depression (PPD) affects up to 20% of mothers and has negative consequences for both mother and child. Although exposure to psychosocial stress during pregnancy and abnormalities in the hypothalamic pituitary adrenal (HPA) axis have been linked to PPD, molecular changes in the brain that contribute to this disease remain unknown. This study utilized a novel chronic psychosocial stress paradigm during pregnancy (CGS) to investigate the effects of psychosocial stress on maternal behavior, neuroendocrine function, and gene expression changes in molecular regulators of the HPA axis in the early postpartum period.

Prolonged methamphetamine exposure during a critical period in neonatal Sprague Dawley rats does not exacerbate egocentric and allocentric learning deficits but increases reference memory impairments.

Children exposed to methamphetamine (MA) in utero have cognitive deficits. MA administration in rats for 5-10 days between postnatal days (P)6 and 20 produces cognitive deficits. The purpose of this study was to determine if extending MA administration by 5 days within P6-20 would exacerbate allocentric (Morris water maze) and egocentric (Cincinnati water maze) learning deficits.