Assessment of adverse childhood experiences in adolescents from a rural agricultural community: Associations with depressive symptoms and psychosocial problems.

The main goal of this study was to determine the prevalence of adverse childhood experiences (ACEs) among Latino adolescents from an agricultural community and to examine how it may impact their neuropsychiatric functioning. This research particularly assessed the association between ACEs and depression, as well as ACEs and psychosocial problems. The study sample consisted of 852 adolescents treated at a rural primary care clinic with a comprehensive ACE screening protocol that assesses for ACEs, depressed mood, and psychosocial functioning during every annual Well-Child Visit.

Learning and memory deficits produced by aspartame are heritable via the paternal lineage.

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.

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala.

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.

Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex.

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 (-Cre) or from developing telencephalic glutamatergic neurons (-Cre).

Mindfulness based art therapy study protocol to determine efficacy in reducing college stress and anxiety.

Background: College students in Generation Z are among the most stressed of our time. Previous research suggests that current interventions on university campuses are primarily for students in crises, but supportive services like psychoeducation to introduce coping skills are scant. Interventions that take both financial and time pressures into account are needed to address the mental health challenges faced by students.

Long-term functional alterations following prenatal GLP-1R activation.

Evidence supporting the use of glucagon-like peptide-1 (GLP-1) analogues to pharmacologically treat disorders beyond type 2 diabetes and obesity is increasing. However, little is known about how activation of the GLP-1 receptor (GLP-1R) during pregnancy affects maternal and offspring outcomes. We treated female C57Bl/6 J mice prior to conception and throughout gestation with a long-lasting GLP-1R agonist, Exendin-4.

Dysregulation of brain dopamine systems in major depressive disorder.

Major depressive disorder (MDD or depression) is a debilitating neuropsychiatric syndrome with genetic, epigenetic, and environmental contributions. Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. A wide array of cellular and molecular modifications distributed across a variety of neuronal processes and circuits underlie the pathophysiology of depression-no established mechanism can explain all aspects of the disease.

GLP-1R activation alters performance in cognitive tasks in a sex-dependent manner.

Rationale: The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been purported to have antidepressant-like and cognitive-enhancing effects. Many people suffering from major depressive disorder (MDD) also experience deficits in cognition. While currently approved antidepressant pharmacotherapies can alleviate the mood symptoms in some patients, they do not treat the cognitive ones.

A novel mouse model of glucagon-like peptide-1 receptor expression: A look at the brain.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a number of functions to maintain energy homeostasis and contribute to motivated behavior, both peripherally and within the central nervous system (CNS). These functions, which include insulin secretion, gastric emptying, satiety, and the hedonic aspects of food and drug intake, are primarily mediated through stimulation of the GLP-1 receptor. While this receptor plays an important role in a variety of physiological outcomes, data regarding its CNS expression has been primarily limited to regional receptor binding and single-label transcript expression studies.

Biobehavioral utility of mindfulness-based art therapy: Neurobiological underpinnings and mental health impacts.

Unlabelled: Mindfulness-based art therapy (MBAT) combines mindfulness practices with art therapy to promote health, wellness, and adaptive responses to stress. Mindfulness-based stress reduction programs have been demonstrated to reduce anxiety symptoms in people with generalized anxiety disorder and serious medical conditions such as cancer. However, the benefits of MBAT specifically—not just in clinical anxiety disorders, but also for routine day-to-day anxiousness—have received little attention until recently.

Developmental opioid exposures: Neurobiological underpinnings, behavioral impacts, and policy implications.

Unlabelled: The devastating impact of opioid abuse and dependence on the individual, family, and society are well known but extremely difficult to combat. During pregnancy, opioid drugs and withdrawal also affect fetal brain development and newborn neural functions, in addition to maternal effects. Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome (NAS/NOWS) rates have drastically increased in the US in the past decade.

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice.

The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2 mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors.

Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell cytokine production in vivo.

Background: IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and T2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells.

Functional coding variation in the presynaptic dopamine transporter associated with neuropsychiatric disorders drives enhanced motivation and context-dependent impulsivity in mice.

Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val.

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.

Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo.

Cocaine-induced neurodevelopmental deficits and underlying mechanisms.

Exposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior.

The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc).

Deletion of Gαq in the telencephalon alters specific neurobehavioral outcomes.

G(αq) -coupled receptors are ubiquitously expressed throughout the brain and body, and it has been shown that these receptors and associated signaling cascades are involved in a number of functional outputs, including motor function and learning and memory. Genetic alterations to G(αq) have been implicated in neurodevelopmental disorders such as Sturge-Weber syndrome. Some of these associated disease outcomes have been modeled in laboratory animals, but as G(αq) is expressed in all cell types, it is difficult to differentiate the underlying circuitry or causative neuronal population.

New tools for the quantitative assessment of prodrug delivery and neurotoxicity.

Systemic off-target toxicities, including neurotoxicity, are prevalent side effects in cancer patients treated with a number of otherwise highly efficacious anticancer drugs. In the current study, we have: (1) developed a new analytical metric for the in vivo preclinical assessment of systemic toxicities/neurotoxicity of new drugs and delivery systems; and (2) evaluated, in mice, the in vivo efficacy and toxicity of a versatile and modular NanoDendron (ND) drug delivery and imaging platform that we recently developed. Our paclitaxel-carrying ND prodrug, ND(PXL), is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy.

CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling.

Aims: Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation.

Results: We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTEN-inducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals.

Loss of dopamine D2 receptors increases parvalbumin-positive interneurons in the anterior cingulate cortex.

Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected.

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release.

Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis.

Insulin signaling in the central nervous system (CNS) regulates energy balance and peripheral glucose homeostasis. Rictor is a key regulatory/structural subunit of the mTORC2 complex and is required for hydrophobic motif site phosphorylation of Akt at serine 473. To examine the contribution of neuronal Rictor/mTORC2 signaling to CNS regulation of energy and glucose homeostasis, we utilized Cre-LoxP technology to generate mice lacking Rictor in all neurons, or in either POMC or AgRP expressing neurons.

Developmental consequences of fetal exposure to drugs: what we know and what we still must learn.

Most drugs of abuse easily cross the placenta and can affect fetal brain development. In utero exposures to drugs thus can have long-lasting implications for brain structure and function. These effects on the developing nervous system, before homeostatic regulatory mechanisms are properly calibrated, often differ from their effects on mature systems.