In a circuit necessary for cognition and emotional affect, Alzheimer's-like pathology associates with neuroinflammation, cognitive and motivational deficits in the young adult TgF344-AD rat.

In addition to extracellular amyloid plaques, intracellular neurofibrillary tau tangles, and inflammation, cognitive and emotional affect perturbations are characteristic of Alzheimer's disease (AD). The cognitive and emotional domains impaired by AD include several forms of decision making (such as intertemporal choice), blunted motivation (increased apathy), and impaired executive function (such as working memory and cognitive flexibility). However, the interaction between these domains of the mind and their supporting neurobiological substrates at prodromal stages of AD, or whether these interactions can be predictive of AD severity (individual variability), remain unclear.

Impairments in Fear Extinction Memory and Basolateral Amygdala Plasticity in the TgF344-AD Rat Model of Alzheimer's Disease Are Distinct from Nonpathological Aging.

Fear-based disorders such as post-traumatic stress disorder (PTSD) steepen age-related cognitive decline and double the risk for developing Alzheimer's disease (AD). Because of the seemingly hyperactive properties of fear memories, PTSD symptoms can worsen with age. Perturbations in the synaptic circuitry supporting fear memory extinction are key neural substrates of PTSD.

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease.

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer's disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC-NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation.

Altered DNA Methylation in the Developing Brains of Rats Genetically Prone to High versus Low Anxiety.

There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder [LR]) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats.

Perinatal exposure to the SSRI paroxetine alters the methylome landscape of the developing dentate gyrus.

Evidence in humans and rodents suggests that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can have serious long-term consequences in offspring exposed in utero or infancy via breast milk. In spite of this, there is limited knowledge of how perinatal SSRI exposure impacts brain development and adult behaviour. Children exposed to SSRIs in utero exhibit increased internalizing behaviour and abnormal social behaviour between the ages of 3 and 6, and increased risk of depression in adolescence; however, the neurobiological changes underlying this behaviour are poorly understood.

A paternal methyl donor depleted diet leads to increased anxiety- and depression-like behavior in adult rat offspring.

Epigenetic mechanisms such as DNA methylation elicit lasting changes in gene expression and likely mediate gene-environment interactions that shape brain development, behavior, and emotional health. Myriad environmental factors influence DNA methylation, including methyl donor content in the paternal diet, could influence methylation in offspring via changes in the paternal germ line. The present study examines the effects of paternal methyl donor dietary deficiency on offspring's emotional behaviors, including anxiety, social interaction, and depression-like behavior.

Amygdalar expression of the microRNA miR-101a and its target Ezh2 contribute to rodent anxiety-like behaviour.

A greater understanding of neural mechanisms contributing to anxiety is needed in order to develop better therapeutic interventions. This study interrogates a novel molecular mechanism that shapes anxiety-like behaviour, demonstrating that the microRNA miR-101a-3p and its target, enhancer of zeste homolog 2 (Ezh2) in the amygdala, contribute to rodent anxiety-like behaviour. We utilized rats that were selectively bred for differences in emotionality and stress reactivity, showing that high-novelty-responding (HR) rats, which display low trait anxiety, have lower miR-101a-3p levels in the amygdala compared to low-novelty-responding (LR) rats that characteristically display high trait anxiety.

Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala.

Understanding biological mechanisms that shape vulnerability to emotional dysfunction is critical for elucidating the neurobiology of psychiatric illnesses like anxiety and depression. To elucidate molecular and epigenetic alterations in the brain that contribute to individual differences in emotionality, our laboratory utilized a rodent model of temperamental differences. Rats bred for low response to novelty (Low Responders, LRs) are inhibited in novel situations and display high anxiety, helplessness, and diminished sociability compared to High Novelty Responder (HR) rats.

Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats.

Chronic stress triggers a variety of physical and mental health problems, and how individuals cope with stress influences risk for emotional disorders. To investigate molecular mechanisms underlying distinct stress coping styles, we utilized rats that were selectively-bred for differences in emotionality and stress reactivity. We show that high novelty responding (HR) rats readily bury a shock probe in the defensive burying test, a measure of proactive stress coping behavior, while low novelty responding (LR) rats exhibit enhanced immobility, a measure of reactive coping.

Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior.

Individual differences in human temperament can increase the risk of psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats.

Inborn stress reactivity shapes adult behavioral consequences of early-life maternal separation stress.

Early-life experience strongly impacts neurodevelopment and stress susceptibility in adulthood. Maternal separation (MS), an established model of early-life adversity, has been shown to negatively impact behavioral and endocrine responses to stress in adulthood. However, the impact of MS in rats with heightened inborn stress susceptibility has not been fully explored.

Learned helplessness and social avoidance in the Wistar-Kyoto rat.

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation.

The human IGF1R IRES likely operates through a Shine-Dalgarno-like interaction with the G961 loop (E-site) of the 18S rRNA and is kinetically modulated by a naturally polymorphic polyU loop.

IGF1R is a proto-oncogene with potent mitogenic and antiapoptotic activities, and its expression must be tightly regulated to maintain normal cellular and tissue homeostasis. We previously demonstrated that translation of the human IGF1R mRNA is controlled by an internal ribosome entry site (IRES), and delimited the core functional IRES to a 90-nucleotide segment of the 5'-untranslated region positioned immediately upstream of the initiation codon. Here we have analyzed the sequence elements that contribute to the function of the core IRES.

Northwestern profiling of potential translation-regulatory proteins in human breast epithelial cells and malignant breast tissues: evidence for pathological activation of the IGF1R IRES.

Genes involved in the control of cell proliferation and survival (those genes most important to cancer pathogenesis) are often specifically regulated at the translational level, through RNA-protein interactions involving the 5'-untranslated region of the mRNA. IGF1R is a proto-oncogene strongly implicated in human breast cancer, promoting survival and proliferation of tumor cells, as well as metastasis and chemoresistance. Our lab has focused on the molecular mechanisms regulating IGF1R expression at the translational level.

mrtl-A translation/localization regulatory protein encoded within the human c-myc locus and distributed throughout the endoplasmic and nucleoplasmic reticular network.

mrtl (myc-related translation/localization regulatory factor) is a previously uncharacterized protein synthesized from the first open reading frame contained within the human c-myc P0 transcript, approximately 800 nucleotides upstream of the Myc coding sequence. The mrtl protein, 114 amino acids in length, is projected to contain an N-terminal transmembrane domain and a highly charged C-terminal interaction domain with homology to numerous RNA-binding proteins. Using monoclonal antibodies raised against the hydrophilic C-terminal domain, endogenous mrtl was visualized in human breast tumor cell lines and primary mammary epithelial cells at the nuclear envelope and contiguous endoplasmic/nucleoplasmic reticulum.

Alterations in RNA-binding activities of IRES-regulatory proteins as a mechanism for physiological variability and pathological dysregulation of IGF-IR translational control in human breast tumor cells.

The type I insulin-like growth factor receptor (IGF-IR) is integrally involved in the control of cellular proliferation and survival. An internal ribosomal entry site (IRES) within the 1,038 nucleotide 5'-untranslated region of the human IGF-IR mRNA helps to provide the tight control of IGF-IR expression necessary for maintenance of normal cellular and tissue homeostasis. The IRES maps to a discrete sequence of 85 nucleotides positioned just upstream of the IGF-IR initiation codon, allowing the ribosome to bypass the highly structured regions of the 5'-UTR as well as the upstream open reading frame.

The ELAV RNA-stability factor HuR binds the 5'-untranslated region of the human IGF-IR transcript and differentially represses cap-dependent and IRES-mediated translation.

The type I insulin-like growth factor receptor (IGF-IR) is an integral component in the control of cell proliferation, differentiation and apoptosis. The IGF-IR mRNA contains an extraordinarily long (1038 nt) 5'-untranslated region (5'-UTR), and we have characterized a diverse series of proteins interacting with this RNA sequence which may provide for intricate regulation of IGF-IR gene expression at the translational level. Here, we report the purification and identification of one of these IGF-IR 5'-UTR-binding proteins as HuR, using a novel RNA crosslinking/RNase elution strategy.