Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior

Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms

Optogenetic Strategies to Dissect the Neural Circuits that Underlie Reward and Addiction

Optogenetic strategies for perturbation of neural circuit function have begun to revolutionize systems neuroscience. Whereas optogenetics has proven to be a powerful approach for studying neural systems, the tools to conduct these experiments are still continuously evolving. Here we briefly summarize available hardware and reagents that can be used for studying behaviors related to reward and addiction. In addition, we discuss recent studies in which these strategies have been applied to study neural circuit function in brain slices as well as awake and behaving animals. Collectively, this work serves as a brief introduction to optogenetic techniques and highlights how these tools can be applied to elucidate the neural circuits that underlie reward processing and addiction

Integrating Optogenetic and Pharmacological Approaches to Study Neural Circuit Function: Current Applications and Future Directions

Optogenetic strategies to control genetically distinct populations of neurons with light have been rapidly evolving and widely adopted by the neuroscience community as one of the most important tool sets to study neural circuit function. Although optogenetics have already reshaped neuroscience by allowing for more precise control of circuit function compared with traditional techniques, current limitations of these approaches should be considered. Here, we discuss several strategies that combine optogenetic and contemporary pharmacological techniques to further increase the specificity of neural circuit manipulation. We also discuss recent advances that allow for the selective modulation of cellular function and gene expression with light. In addition, we outline a novel application of optogenetic circuit analysis for causally addressing the role of pathway-specific neural activity in mediating alterations in postsynaptic transcriptional processing in genetically defined neurons. By determining how optogenetic activation of specific neural circuits causally contributes to alterations in gene expression in a high-throughput fashion, novel biologic targets for future pharmacological intervention may be uncovered. Lastly, extending this experimental pipeline to selectively target pharmacotherapies to genetically defined neuronal populations or circuits will not only provide more selective control of neural circuits, but also may lead to the development of neural circuit specific pharmacological therapeutics

Design and Commissioning of the ISAC Control System at TRIUMF

The control system for the initial stage of the ISAC radioactive beam facility at TRIUMF was recently commissioned and the facility delivered the first radioactive beam to users in December of 1998. The control system is based on the EPICS toolkit. VME based Motorola MVME162 CPUs serve as input/output Controllers, SUN workstations as application servers, and PCs are used with X-terminal software as operator interface stations. Modicon PLCs control the vacuum system and ion sources. A network of CAN-bus based controllers is used for the beam guidance system. Custom VME modules were developed for beam diagnostics. 1 ISAC ISAC, an Online Isotope Separator and ACcelerator, is being built at TRIUMF and provided the first beams of short-lived radioactive isotopes to experiments in December of 1998. At present, ISAC is the world’s most intense source of low energy radioactive beams. By the end of next year it will also deliver the world’s most energetic radioactive beams (1.5 MeV/u). A 500 MeV proton beam of up to 10 µA from the TRIUMF cyclotron produces short-lived radioactive species in a hot (2000 °C) production target. They are extracted and accelerated to 60 keV in a target-ion-source and pass through a magnetic pre-separator before being isotopically separated in a high-resolution mass separator. This radioactive beam can either feed the low-energy experimental area or be further accelerated in a 19-ring radio-frequency quadrupole (RFQ) followed by a five-tank drift tube linac (DTL). For tuning purposes, an off-line ion source provides non-radioactive beams

Single centre experience of the application of self navigated 3D whole heart cardiovascular magnetic resonance for the assessment of cardiac anatomy in congenital heart disease.

BACKGROUND: For free-breathing cardiovascular magnetic resonance (CMR), the self-navigation technique recently emerged, which is expected to deliver high-quality data with a high success rate. The purpose of this study was to test the hypothesis that self-navigated 3D-CMR enables the reliable assessment of cardiovascular anatomy in patients with congenital heart disease (CHD) and to define factors that affect image quality. METHODS: CHD patients ≥2 years-old and referred for CMR for initial assessment or for a follow-up study were included to undergo a free-breathing self-navigated 3D CMR at 1.5T. Performance criteria were: correct description of cardiac segmental anatomy, overall image quality, coronary artery visibility, and reproducibility of great vessels diameter measurements. Factors associated with insufficient image quality were identified using multivariate logistic regression. RESULTS: Self-navigated CMR was performed in 105 patients (55% male, 23 ± 12y). Correct segmental description was achieved in 93% and 96% for observer 1 and 2, respectively. Diagnostic quality was obtained in 90% of examinations, and it increased to 94% if contrast-enhanced. Left anterior descending, circumflex, and right coronary arteries were visualized in 93%, 87% and 98%, respectively. Younger age, higher heart rate, lower ejection fraction, and lack of contrast medium were independently associated with reduced image quality. However, a similar rate of diagnostic image quality was obtained in children and adults. CONCLUSION: In patients with CHD, self-navigated free-breathing CMR provides high-resolution 3D visualization of the heart and great vessels with excellent robustness

The Inhibitory Circuit Architecture of the Lateral Hypothalamus Orchestrates Feeding

The growing prevalence of overeating disorders is a key contributor to the worldwide obesity epidemic. Dysfunction of particular neural circuits may trigger deviations from adaptive feeding behaviors. The lateral hypothalamus (LH) is a crucial neural substrate for motivated behavior including feeding, but the precise functional neurocircuitry that controls LH neuronal activity to engage feeding has not been defined. We observed that inhibitory synaptic inputs from the extended amygdala preferentially innervate and suppress the activity of LH glutamatergic neurons to control food intake. These findings help explain how dysregulated activity at a number of unique nodes can result in a cascading failure within a defined brain network to produce maladaptive feeding

Activation of Prefrontal Cortical Parvalbumin Interneurons Facilitates Extinction of Reward-Seeking Behavior

Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PV+ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PV+ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PV+ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PV+ FSIs may enhance reward-related behavioral flexibility

Preferential Enhancement of Dopamine Transmission within the Nucleus Accumbens Shell by Cocaine Is Attributable to a Direct Increase in Phasic Dopamine Release Events

Preferential enhancement of dopamine transmission within the nucleus accumbens (NAc) shell is a fundamental aspect of the neural regulation of cocaine reward. Despite its importance, the nature of this effect is poorly understood. Here, we used fast-scan cyclic voltammetry to examine specific transmission processes underlying cocaine-evoked increases in dopamine transmission within the NAc core and shell. Initially, we examined altered terminal dopamine concentrations following global autoreceptor blockade. This was the first examination of autoreceptor regulation of naturally occurring phasic dopamine transmission and provided a novel characterization of specific components of dopamine neurotransmission. Comparison of increased dopamine signaling evoked by autoreceptor blockade and cocaine administration allowed robust resolution between increased frequency, concentration, and duration of phasic dopamine release events following cocaine delivery. Cocaine increased dopamine transmission by slowed uptake and increased concentration of dopamine released in the core and shell. However, an additional increase in the number phasic release events occurred only within the NAc shell and this increase was eliminated by inactivation of midbrain dopaminergic neurons. This represents the first evidence that cocaine directly increases the frequency of dopamine release events and reveals that this is responsible for preferentially increased dopamine transmission within the NAc shell following cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration and sub-region differences were abolished when cocaine was administered in the absence of autoregulation. Together, these results demonstrate that cocaine administration results in a temporally and regionally specific increase in phasic dopamine release that is significantly regulated by dopamine autoreceptors