Valence and salience encoding by parallel circuits from the paraventricular thalamus to the nucleus accumbens.

The anterior and posterior subregions of the paraventricular thalamus (aPVT and pPVT, respectively) play unique roles in learned behaviors, from fear conditioning to alcohol/drug intake, potentially through differentially organized projections to limbic brain regions including the nucleus accumbens medial shell (mNAcSh). Here, we found that the aPVT projects broadly to the mNAcSh and that the aPVT-mNAcSh circuit encodes positive valence, such that manipulations of the circuit modulated both innately programmed and learned behavioral responses to positively and negatively valenced stimuli, particularly in females. Further, the endogenous activity of aPVT presynaptic terminals in the mNAcSh was greater in response to positively than negatively valenced stimuli, and the probability of synaptic glutamate release from aPVT neurons in the mNAcSh was higher in females than males.

The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice.

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNST neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNST neurons but also engages a large BNST interneuron population to ultimately inhibit BNST neurons, and this polysynaptic PVT-BNST circuit is more robust in females than males.

Influences of Stress and Sex on the Paraventricular Thalamus: Implications for Motivated Behavior.

The paraventricular nucleus of the thalamus (PVT) is a critical neural hub for the regulation of a variety of motivated behaviors, integrating stress and reward information from environmental stimuli to guide discrete behaviors several limbic projections. Neurons in the PVT are activated by acute and chronic stressors, however several roles of the PVT in behavior modulation emerge only following repeated stress exposure, pointing to a role for hypothalamic pituitary adrenal (HPA) axis modulation of PVT function. Further, there may be a reciprocal relationship between the PVT and HPA axis in which chronic stress-induced recruitment of the PVT elicits an additional role for the PVT to regulate motivated behavior by modulating HPA physiology and thus the neuroendocrine response to stress itself.

Adolescent stress sensitizes the adult neuroimmune transcriptome and leads to sex-specific microglial and behavioral phenotypes.

Adolescent exposure to chronic stress, a risk factor for mood disorders in adulthood, sensitizes the neuroinflammatory response to a subsequent immune challenge. We previously showed that chronic adolescent stress (CAS) in rats led to distinct patterns of neuroimmune priming in adult male and female rats. However, sex differences in the neuroimmune consequences of CAS and their underlying mechanisms are not fully understood.

Chronic adolescent stress sex-specifically alters the hippocampal transcriptome in adulthood.

Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor.

Chronic adolescent stress sex-specifically alters central and peripheral neuro-immune reactivity in rats.

Adversity during development is a reliable predictor of psychiatric disorders such as depression and anxiety which are increasingly recognized to have an immune component. We have previously demonstrated that chronic adolescent stress (CAS) in rats leads to depressive-like behavior in adulthood along with long-lasting changes to the hypothalamic-pituitary-adrenal axis and pro-inflammatory cytokine induction in the hippocampus. However, the mechanisms by which CAS promotes hippocampal inflammation are not yet defined.

Measuring corticosterone concentrations over a physiological dynamic range in female rats.

Accurate assessment of plasma corticosterone, the primary stress hormone in rodents, is an essential part of characterizing the stress response in experimental animals. To this end, both enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) remain widely used. However, considerable assay-specific variability exists among commercially available corticosterone assays due to differing assay principles, detection methods, range, and sensitivity.

Locomotor sensitization to cocaine in adolescent and adult female Wistar rats.

Adolescent stress exposure is a risk factor for drug abuse, and sex differences contribute to psychostimulant responses. Although many studies have utilized the Wistar rat strain in adolescent stress paradigms, the impact of adolescent stress exposure on addiction-like outcomes has not been rigorously tested in female Wistar rats. In this study, locomotor sensitization was assessed in adolescent and adult female Wistar rats following either chronic stress during adolescence (CAS) or no stress (NS).

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad.

Mutual regulation and balance between the endocrine and immune systems facilitate an organism's stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior.

Neuroinflammation and Behavior in HIV-1 Transgenic Rats Exposed to Chronic Adolescent Stress.

Highly active antiretroviral therapy (HAART) has improved prognosis for people living with HIV (PLWH) and dramatically reduced the incidence of AIDS. However, even when viral load is controlled, PLWH develop psychiatric and neurological disorders more frequently than those living without HIV. Adolescents with HIV are particularly susceptible to the development of psychiatric illnesses and neurocognitive impairments.

Pharmacological stimulation of hypoxia inducible factor-1α facilitates the corticosterone response to a mild acute stressor.

While both glucocorticoids (the principal output of the hypothalamic-pituitary-adrenal axis) and oxidative stress have been implicated in outcomes due to an excessive or prolonged stress response, the precise mechanisms linking these two systems remain poorly elucidated. One potential mediator between the hypothalamic-pituitary-adrenal axis and oxidative stress is the hypoxia inducible factor-1 (HIF-1) pathway. HIF-1 is an oxygen-responsive transcription factor with diverse effects including changes in cellular metabolism.

Demonstration of ATP-dependent, transcellular transport of lipid across the lymphatic endothelium using an in vitro model of the lacteal.

Purpose: The lymphatic system plays crucial roles in tissue fluid balance, trafficking of immune cells, and the uptake of dietary lipid from the intestine. Given these roles there has been an interest in targeting lymphatics through oral lipid-based formulations or intradermal delivery of drug carrier systems. However the mechanisms regulating lipid uptake by lymphatics remain unknown.

Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy.