Substantial decline of phasic dopamine signaling in senescent male rats does not impact dopamine-dependent Pavlovian conditioning.

Normal aging is associated with cognitive decline which impacts financial decision making. One of the underlying features of decision making is probability estimation, in which nucleus accumbens dopamine signaling has been implicated. Here we used fast-scan cyclic voltammetry to probe for age differences in dopamine signaling, and pharmacological manipulation to test for age differences in the dopamine dependence of Pavlovian conditioning.

Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist.

Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testing native molecules (NMU or its truncated version NMU-8) in a tissue-specific manner, in effect, taking advantage of the distinct receptor expression profiles. These strategies have proved quite useful despite the inherent limitations of overlapping receptor roles and potential compensatory influences of germline gene deletion.

Profiling mouse brown and white adipocytes to identify metabolically relevant small ORFs and functional microproteins.

Microproteins (MPs) are a potentially rich source of uncharacterized metabolic regulators. Here, we use ribosome profiling (Ribo-seq) to curate 3,877 unannotated MP-encoding small ORFs (smORFs) in primary brown, white, and beige mouse adipocytes. Of these, we validated 85 MPs by proteomics, including 33 circulating MPs in mouse plasma.

Management of hospitalized patients with mild to moderate diabetic ketoacidosis using a continuous insulin infusion protocol on a medical surgical ward and observation level of care: A retrospective cohort study.

Although the practice of using rapid-acting subcutaneous insulin for the management of mild-to-moderate diabetic ketoacidosis is becoming increasingly popular, the continuous insulin infusion remains widely utilized, and its real-world applicability and safety on a medical surgical unit (Med Surg) and observation level of care are unclear. We assessed whether a continuous insulin infusion protocol for mild-to-moderate diabetic ketoacidosis on Med Surg/observation level of care over a 6.5-year period was associated with adverse outcomes.

Whole transcriptome analysis and validation of metabolic pathways in subcutaneous adipose tissues during FGF21-induced weight loss in non-human primates.

Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. In mice, FGF21 is thought to cause weight loss by stimulating thermogenesis, but whether FGF21 increases energy expenditure (EE) in primates is unclear. Here, we explore the transcriptional response and gene networks active in adipose tissue of rhesus macaques following FGF21-induced weight loss.

Roundabout receptor 2 maintains inhibitory control of the adult midbrain.

The maintenance of excitatory and inhibitory balance in the brain is essential for its function. Here we find that the developmental axon guidance receptor Roundabout 2 (Robo2) is critical for the maintenance of inhibitory synapses in the adult ventral tegmental area (VTA), a brain region important for the production of the neurotransmitter dopamine. Following selective genetic inactivation of in the adult VTA of mice, reduced inhibitory control results in altered neural activity patterns, enhanced phasic dopamine release, behavioral hyperactivity, associative learning deficits, and a paradoxical inversion of psychostimulant responses.

A Central Amygdala CRF Circuit Facilitates Learning about Weak Threats.

Fear is a graded central motive state ranging from mild to intense. As threat intensity increases, fear transitions from discriminative to generalized. The circuit mechanisms that process threats of different intensity are not well resolved.

Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination.

Protein Kinase A (PKA) mediates synaptic plasticity and is widely implicated in learning and memory. The hippocampal dentate gyrus (DG) is thought to be responsible for processing and encoding distinct contextual associations in response to highly similar inputs. The mossy fiber (MF) axons of the dentate granule cells convey strong excitatory drive to CA3 pyramidal neurons and express presynaptic, PKA-dependent forms of plasticity.

Novel indole-based compounds that differentiate alkylindole-sensitive receptors from cannabinoid receptors and microtubules: Characterization of their activity on glioma cell migration.

Indole-based compounds, such as the alkyl-indole (AI) compound WIN55212-2, activate the cannabinoid receptors, CB and CB, two well-characterized G protein-coupled receptors (GPCR). Reports indicate that several indole-based cannabinoid agonists, including WIN55212-2, lack selectivity and interact with at least two additional targets: AI-sensitive GPCRs and microtubules. Studying how indole-based compounds modulate the activity of these 4 targets has been difficult as selective chemical tools were not available.

Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing.

Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training.

Dopamine is highly implicated both as a teaching signal in reinforcement learning and in motivating actions to obtain rewards. However, theoretical disconnects remain between the temporal encoding properties of dopamine neurons and the behavioral consequences of its release. Here, we demonstrate in rats that dopamine evoked by Pavlovian cues increases during acquisition, but dissociates from stable conditioned appetitive behavior as this signal returns to preconditioning levels with extended training.

Relationship between the frequency of HIV-specific CD8+ T cells and the level of CD38+CD8+ T cells in untreated HIV-infected individuals.

CD8+ T cells are critical for effective host defenses against viral infections. Studies addressing HIV-induced immune responses in infected individuals have suggested that CD8+ T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8+ T cells, HIV is not contained in many untreated patients.

Gene expression and viral prodution in latently infected, resting CD4+ T cells in viremic versus aviremic HIV-infected individuals.

The presence of HIV-1 in latently infected, resting CD4(+) T cells has been clearly demonstrated in infected individuals; however, the extent of viral expression and the underlying mechanisms of the persistence of HIV-1 in this viral reservoir have not been fully delineated. Here, we show that resting CD4(+) T cells from the majority of viremic patients are capable of producing cell-free HIV-1 spontaneously ex vivo. The levels of HIV-1 released by resting CD4(+) T cells were not significantly reduced in the presence of inhibitors of cellular proliferation and viral replication.