Neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, and schizophrenia are classically defined by cognitive and sensorimotor impairments. However, dysregulated motivation is a core but underrecognized feature of these conditions with significant implications for quality of life. We present a heuristic hypothesis-generating framework that distinguishes two interacting and partially dissociable subdomains of motivation: self-initiated motivation, defined as goal-directed behavior that arises in the absence of immediate external prompting, and stimulus-driven motivation, defined as responses elicited by environmental cues or physiological states. Unlike traditional distinctions such as intrinsic versus extrinsic motivation or the liking-wanting dichotomy, this framework emphasizes the initiation of motivated action as its organizing axis, focusing on whether behaviors are generated internally or triggered by external stimuli rather than on reward valuation or hedonic impact. These subdomains are implemented by overlapping, dynamically interacting neural circuits that follow relatively distinct developmental trajectories and may exhibit differential sensitivity to early-life adversity. Our model provides a transdiagnostic conceptual scaffold that bridges categorical diagnoses and aligns with the Research Domain Criteria Motivation Systems framework. We focus on disorders with early-emerging circuit vulnerability and developmental onset, while recognizing that the framework is applicable more broadly across psychiatric conditions. Rather than offering a definitive nosology, the model supports mechanistic phenotyping, hypothesis-driven experimental design, and translational inference across neurodevelopmental disorders. To illustrate its translational utility, we highlight behavioral assays in animal models that differentially engage each subdomain and propose circuit-informed, testable strategies to guide future intervention development.

INTRODUCTION:Prenatal alcohol exposure (PAE) can lead to a wide spectrum of deficits in growth and neurological function, and there is an established link between PAE and auditory dysfunction. However, the effects of PAE on auditory development are complex and vary depending on the age and pattern of alcohol exposure. METHODS:In this study, we developed a mouse model of PAE during the first half of the gestational period, mimicking alcohol consumption during the first trimester of pregnancy in humans. RESULTS:This exposure did not affect overall growth or induce anxiety-related symptoms in the offspring, as indicated by normal body weight change and largely unchanged behaviors in the open field and elevated zero maze tests. However, several aspects of auditory function were affected by PAE. Offspring born from prenatal alcohol-exposed dams displayed smaller auditory brainstem responses (ABRs) at 2-month-old as compared to those from control dams, suggesting weakened neuron synchronization within auditory brainstem circuits. Additionally, a reduction in the reproducibility of ABR peaks III/IV was observed in PAE offspring. In contrast, the overall hearing sensitivity and neuron transmission was not affected by PAE, as evaluated by ABR thresholds or peak latencies. In an acoustic startle test, PAE offspring failed to display prepulse inhibition to low levels of prepulses more frequently than control offspring at both 2 weeks old and 2 months old, suggesting an early-onset and lasting deficit in auditory gating or sound level differentiation. CONCLUSION:These results demonstrate that mice exposed to alcohol during early gestation have largely preserved auditory responses but show significant alterations in specific features of auditory processing.

Adeno-associated viruses (AAV) are promising vectors for gene therapy due to their efficacy in vivo. However, there is room for improvement to address key limitations such as the pre-existing immunity to AAV in patients, high-dose toxicity, and relatively low efficiency for some cell types. This study introduces a metabolic engineering approach, using knockout of the enzyme phosphatidylserine synthase 1 (PTDSS1) to increase the abundance of extracellular vesicle-enclosed AAV (EV-AAV) relative to free AAV in the supernatant of producer cells, simplifying downstream purification processes. The lipid-engineered HEK293T-ΔPTDSS1 cell line achieved a 42.7-fold enrichment of EV-AAV9 compared to free AAV9 in the supernatant. The rational genetic strategy also led to a 300-fold decrease of free AAV in supernatant compared to wild-type HEK293T. The membrane-engineered EV-AAV9 (mEV-AAV9) showed unique envelope composition alterations, including cholesterol enrichment and improved transduction efficiency in human AC16 cardiomyocytes by 1.5-fold compared to conventional EV-AAV9 and by 11-fold compared to non-enveloped AAV9. Robust in-vivo transduction four weeks after intraparenchymal administration of mEV-AAV9 was observed in the murine brain. This study shows promise in the potential of lipid metabolic engineering strategies to improve the efficiency and process development of enveloped gene delivery vectors.

Prenatal nicotine exposure is linked to adverse neurodevelopmental outcomes, yet e-cigarette use during pregnancy continues to rise due to aggressive marketing efforts and misconceptions of safety. We investigated the effect of prenatal e-cigarette aerosol exposure on the migration of GABA neurons, a developmental process critical for the establishment of cerebral cortical circuitry. Pregnant mice were exposed to nicotine-containing aerosol (e-cigarette), nicotine-free aerosol (e-liquid) or room air (control) daily beginning 2 weeks before conception and continuing until gestational day 14. E-cigarette, but not e-liquid, aerosol significantly reduced GABA neuron density in the dorsal cerebral wall at rostral forebrain level and within the marginal zone, reflecting region-specific vulnerabilities. In vitro explant cultures revealed that nicotine dose-dependently reduced neuronal migration, and this effect was mimicked by a selective α7 nicotinic acetylcholine receptor (nAChR) agonist. Blocking the α7 nAChR using a selective antagonist attenuated the effects of nicotine on neuronal migration. These findings reveal a previously unrecognized vulnerability of GABA neuron migration to e-cigarette aerosol and identify α7 nAChR activation as a mechanism for nicotine-induced impairment of GABA neuron migration. Moreover, the findings highlight the need for translational efforts to update clinical guidance and public policy regarding e-cigarette use during pregnancy.

IntroductionFragile X syndrome is an inherited X-linked disorder associated with intellectual disabilities that begin in childhood and last a lifetime. The symptoms overlap with autism spectrum disorder, and the syndrome predominantly affects males. Consequently, FXS research tends to favor analysis of social behaviors in males, leaving a gap in our understanding of other behavioral traits, especially in females.MethodsWe used a mouse model of FXS to analyze developmental, behavioral, neurochemical, and transcriptomic profiles in males and females.ResultsOur behavioral assays demonstrated locomotor hyperactivity, motor impulsivity, increased “approach” behavior in an approach-avoidance assay, and deficits in nest building behavior. Analysis of brain neurotransmitter content revealed deficits in striatal GABA, glutamate, and serotonin content. RNA sequencing of the ventral striatum unveiled expression changes associated with neurotransmission as well as motivation and substance use pathways. Sex differences were identified in nest building behavior, striatal neurotransmitter content, and ventral striatal gene expression.DiscussionIn summary, our study identified sex differences in specific behavioral, neurotransmitter, and gene expression phenotypes and gene set enrichment analysis identified significant enrichment of pathways associated with motivation and drug reward.

Objective: We offer an overview of ADHD research using mouse models of nicotine exposure. Method: Nicotine exposure of C57BL/6 or Swiss Webster mice occurred during prenatal period only or during the prenatal and the pre-weaning periods. Behavioral, neuroanatomical and neurotransmitter assays were used to investigate neurobiological mechanisms of ADHD and discover candidate ADHD medications. Results: Our studies show that norbinaltorphimine, a selective kappa opioid receptor antagonist is a candidate novel non-stimulant ADHD treatment and that a combination of methylphenidate and naltrexone has abuse deterrent potential with therapeutic benefits for ADHD. Other studies showed transgenerational transmission of ADHD-associated behavioral traits and demonstrated that interactions between untreated ADHD and repeated mild traumatic brain injury produced behavioral traits not associated with either condition alone. Conclusion: Preclinical models contribute to novel insights into ADHD neurobiology and are valuable tools for drug discovery and translation to benefit humans with ADHD.

Environmental exposures produce heritable traits that can linger in the population for one or two generations. Millions of individuals consume substances such as artificial sweeteners daily that are declared safe by regulatory agencies without evaluation of their potential heritable effects. We show that consumption of aspartame, an FDA-approved artificial sweetener, daily for up to 16-weeks at doses equivalent to only 7–15% of the FDA recommended maximum daily intake value (equivalent to 2–4 small, 8 oz diet soda drinks per day) produces significant spatial learning and memory deficits in mice. Moreover, the cognitive deficits are transmitted to male and female descendants along the paternal lineage suggesting that aspartame’s adverse cognitive effects are heritable, and that they are more pervasive than current estimates, which consider effects in the directly exposed individuals only. Traditionally, deleterious environmental exposures of pregnant and nursing women are viewed as risk factors for the health of future generations. Environmental exposures of men are not considered to pose similar risks. Our findings suggest that environmental exposures of men can produce adverse impact on cognitive function in future generations and demonstrate the need for considering heritable effects via the paternal lineage as part of the regulatory evaluations of artificial sweeteners.

Understanding the carcinogenesis mechanism of different carcinogenic agents is paramount for implementing preventive and therapeutic strategies for cancer. Hence, an appropriate simulation of the clinical situation in preclinical studies should be the prime mandate for reaching the validated and pragmatic conclusion. In Asian and Southeast Asian countries, one of the most common etiological agents for oral squamous cell carcinoma (OSCC) is the consumption of betel quid (BQ) with and without tobacco. BQ is marketed in the form of a mixture of various ingredients. It is quite conceivable that when BQ is placed or chewed in the oral cavity, all the carcinogenic components released from different agents get mixed and forms an amalgamation of carcinogens. To further add to the complexity, oral microbial flora also becomes part and parcel of this amalgamation. We envisage the interactions of various carcinogens with each other and the salivary components and microbial flora. However, this clinical scenario is not exactly simulated in various in-vitro experimental studies published in the literature. To better understand the oral carcinogenesis mechanism, it becomes imperative to consider the aforementioned fact in mind while studying carcinogens for oral cancer. In the present commentary, we have made an effort to discuss the amalgamation of the carcinogens in the oral cavity and propose the possible preclinical model to study carcinogens associated with OSCC.

For a very long time, fibres have been employed in building materials. The use of natural and synthetic fibres in prior studies and investigations has yielded promising findings because their presence has proved considerable benefits for the composite material's overall mechanical and physical qualities. The major objectives of this work were the creation of manually crushed interlocking mud bricks and a study of their compressive strength. Mud bricks containing rice husk (1–6% by weight of soil) and wheat straw (1–6 % by weight of soil) were made to accomplish this. Straw husk, a soil additive that varied from 1 to 6 %by weight, was also made by mixing rice husk and wheat straw. Compressive strength analysis was utilized to look at the interlocking mud bricks strength and failure pattern. Bricks made of mud under control had shrinkage cracks, whereas bricks made of fibres did not exhibit any symptoms of shrinkage cracking (wheat straw, rice husk and straw husk). As the number of fibres in the mud brick samples increased, there was a corresponding drop in compressive strength. However, interlocking mud bricks with fibres in them met the minimal strength requirements of several mud brick standards. Therefore, interlocking mud bricks with fibres can be used in earthen building as a long-lasting, cost-effective, and eco-friendly material based on the findings of compressive strength tests.

Generation of mouse models for COVID-19 pathogenesis is of keen interest as they would allow for efficient investigation of disease mechanisms, as well as providing a vaccine and drug development platform. However, the current transgenic hACE2 ...The classical manifestation of COVID-19 is pulmonary infection. After host cell entry via human angiotensin–converting enzyme II (hACE2), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus can infect pulmonary epithelial cells, ...

Use of tobacco products during pregnancy is associated with increased risk for neurodevelopmental disorders in the offspring. Preclinical models of developmental nicotine exposure have offered valuable insights into the neurobiology of nicotine's effects on the developing brain and demonstrated lasting effects of developmental nicotine exposure on brain structure, neurotransmitter signaling and behavior. These models have facilitated discovery of novel compounds as candidate treatments for attention deficit hyperactivity disorder, a neurodevelopmental disorder associated with prenatal nicotine exposure. Using these models the significance of heritability of behavioral phenotypes from the nicotine-exposed pregnant female or adult male to multiple generations of descendants has been demonstrated. Finally, research using the preclinical models has demonstrated synergistic interactions between developmental nicotine exposure and repetitive mild traumatic brain injury that contribute to "worse" outcomes from the injury in individuals with attention deficit hyperactivity disorder associated with developmental nicotine exposure.

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

Attention deficit hyperactivity disorder (ADHD) can be a risk factor for repetitive mild traumatic brain injury (mTBI) or concussions such as those that can occur in contact sports. Individuals with ADHD also appear to have a higher risk of poor neurocognitive outcomes after repetitive mTBI. Findings from clinical studies examining the interactions between ADHD and repetitive mTBI vary, likely because of variabilities in experimental design and outcome measures. We used a mouse model of perinatal nicotine exposure (PNE), which displays behavioral, neuroanatomical, and neurotransmitter features consistent with ADHD and subjected the mice to repetitive mTBI. We used a closed head model of mTBI in awake, unanesthetized mice to mimic concussions in humans. The mTBI was repeated three times daily for seven days. The mice in the PNE-mTBI group took longer to regain consciousness after the mTBI and showed transient novelty-seeking and depression-like behaviors. Before the repetitive mTBI, the mice in the PNE group showed attention deficit, which persisted after the mTBI. The mice in the control (non-PNE) group showed a transient attention deficit after the repetitive mTBI but not any of the other behavioral changes seen in the PNE-mTBI group. These findings from an unanesthetized mouse model with a pre-existing condition show that ADHD and repetitive mTBI together contribute to transient novelty-seeking and depression-like behavior supporting the notion that untreated ADHD may be a risk factor for poor neurocognitive outcomes after concussions.

Introduction: Management of medication regimens and improvement of medication-taking behaviours may require various levels of support, education, engagement and barrier reduction from health services and or pharmacists. The use of dose administration aids (DAAs) may improve medication management for some people, and therefore may facilitate positive health benefits. This Australian study was informed by a literature review that found there was a dearth of data about Aboriginal and Torres Strait Islander peoples' use of DAAs. This study therefore aimed to understand the experiences of Aboriginal and Torres Strait Islander people living on the North Coast of New South Wales with DAAs and if the provision of DAAs supported medication-taking behaviours. Methods: A mixed-methods approach that included data collected from a questionnaire and a series of focus groups was used in this study. Analysis was completed at three stages throughout the study. Results: A total of 30 Aboriginal participants participated in the study. Participants lived in the area ranging from Tweed Heads to Port Macquarie. Twenty-six participants completed the questionnaire and 20 participated in the focus groups; 16 completed both. Participants felt they were managing their medications well. The study noted that, despite this assessment, 45% of focus group participants (9/20) missed taking medications regularly for various reasons. The medication regimens of participants were varied and potentially complex; for example, some participants were taking up to 23 individual doses of oral medications and insulin injections daily as a part of these regimens. Participants described their use of DAAs and how they supported their medication-taking both functionally and financially. Most participants reported that DAAs helped them manage their medications. The weekly or fortnightly provision of DAAs provided regular opportunities for pharmacists to interact with patients and/or their caregivers, supporting improved therapeutic relationships and possibly better health outcomes. Conclusion: DAAs were an important tool for improving medication management for most study participants. DAAs provided affordable and appropriate in-home support for patients to follow prescribed medication regimens. For the participants from this small study who used DAAs and viewed them as an important tool for managing medications, removal of financial subsidies that assist the provision of DAAs to Aboriginal and Torres Strait Islander peoples would have a negative effect on their ability to access them. This in turn may affect their medication-taking behaviours, potentially negatively affecting their long-term health outcomes. Further study regarding the Aboriginal and Torres Strait Islander patient experience of the use of DAAs over a longer period tracking medication adherence, and for a larger cohort of Aboriginal and Torres Strait Islander people, would be beneficial to understanding experience of use of DAAs on a wider scale.

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D ( Grin2d ) and metabotropic receptor 4 ( Grm4 ) and downregulation of the GABA-A receptor associated protein ( Gabarap ) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame’s potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

Attention deficit hyperactivity disorder (ADHD) increases the risk for concussion or mild traumatic brain injury (mTBI). At the same time, recommendations for the management of ADHD include participation in sports and other organized physical activities, including those that carry an increased risk of mTBI. Very little work has been done to determine the extent to which untreated ADHD adversely impacts behavioral outcomes of repeated mild concussions. Here, we used a perinatal nicotine exposure (PNE) mouse model of ADHD combined with a closed-head, repetitive mTBI model. The PNE mouse model carries significant construct, face, and predictive validity as a preclinical model of ADHD. Two-month-old PNE and control mice were subjected to closed-head repetitive mTBI or sham procedure once daily for 5 days. Object-based attention, novel object recognition memory, spatial working memory, and depression-like behavior were analyzed 1 day and 2 weeks following repeated mTBI. Consistent with our previous reports, mice in the PNE group showed significant deficits in object-based attention and working memory prior to mTBI. These deficits persisted following the repeated mTBI. Repeated mTBI produced a transient attention deficit in the control group but did not exacerbate the attention deficit that is characteristic of the PNE group. Although neither PNE nor repetitive mTBI alone influenced immobility in the tail suspension test, when PNE mice were subjected to mTBI, there was a transient increase in this measurement suggesting a synergistic effect of ADHD and mTBI on depression-like behavior. Thus, our data using the PNE mouse model suggest that ADHD may be a risk factor for transient depression following repeated mTBI and that repeated mTBI may be a risk factor for transient attention deficit.

Pradeep G. Bhide – Florida State University, Tallahassee, FL, USA Jean M. Lauder – University of North Carolina, Chapel Hill, NC, USA Carina Mallard – Gothenburg University, Gothenburg, Sweden Richard S. Nowakowski – Florida State University, Tallahassee, FL, USA Debra L. Silver – Duke Institute for Brain Sciences, Durham, NC, USA Gregg D. Stanwood – Florida State University, Tallahassee, FL, USA Francis Szele – University of Oxford, Oxford, UK Sidhartha Tan – Wayne State University, Detroit, MI, USA

Our understanding of the interactions between genetic and environmental factors in shaping behavioral phenotypes has expanded to include environment-induced epigenetic modifications and the intriguing possibility of their association with heritable behavioral phenotypes. The molecular basis of heritability of phenotypes arising from environment-induced epigenetic modifications is not well defined yet. However, phenomenological evidence in favor of it is accumulating rapidly. The resurgence of interest has led to focus on epigenetic modification of germ cells as a plausible mechanism of heritability. Perhaps partly because of practical reasons such as ease of access to male germ cells compared to female germ cells, attention has turned toward heritable effects of environmental influences on male founders. Public health implications of heritable effects of paternal exposures to addictive substances or to psycho-social factors may be enormous. Considering nicotine alone, over a billion people worldwide use nicotine-containing products, and the majority are men. Historically, the adverse effects of nicotine use by pregnant women received much attention by scientists and public policy experts alike. The implications of nicotine use by men for the physical and mental well-being of their children were not at the forefront of research until recently. Here, we review progress in the emerging field of heritable effects of paternal nicotine exposure and its implications for behavioral health of individuals in multiple generations.