NIMH perspectives on future directions in neuroimaging for mental health.

NIMH's mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. New imaging techniques hold great promise for improving our understanding of the pathophysiology of mental illnesses, stratifying patients for treatment selection, and developing a personalized medicine approach. Here, we highlight emerging and promising new technologies that are likely to be vital in helping NIMH accomplish its mission, the potential for utilizing multimodal approaches to study mental illness, and considerations for data analytics and data sharing.

Affective Science Research: Perspectives and Priorities from the National Institutes of Health.

Affective science is a broad and burgeoning field, and the National Institutes of Health (NIH) support research on a similarly broad range of topics. Across NIH, funding is available for basic, translational, and intervention research, including research in non-human animals, healthy populations, and those with or at risk for disease. Multiple NIH Institutes and Centers have specific programs devoted to topics within the affective science umbrella.

Conserved features of anterior cingulate networks support observational learning across species.

The ability to observe, interpret, and learn behaviors and emotions from conspecifics is crucial for survival, as it bypasses direct experience to avoid potential dangers and maximize rewards and benefits. The anterior cingulate cortex (ACC) and its extended neural connections are emerging as important networks for the detection, encoding, and interpretation of social signals during observational learning. Evidence from rodents and primates (including humans) suggests that the social interactions that occur while individuals are exposed to important information in their environment lead to transfer of information across individuals that promotes adaptive behaviors in the form of either social affiliation, alertness, or avoidance.

The Lateral Habenula Circuitry: Reward Processing and Cognitive Control.

There has been a growing interest in understanding the role of the lateral habenula (LHb) in reward processing, affect regulation, and goal-directed behaviors. The LHb gets major inputs from the habenula-projecting globus pallidus and the mPFC, sending its efferents to the dopaminergic VTA and SNc, serotonergic dorsal raphe nuclei, and the GABAergic rostromedial tegmental nucleus. Recent studies have made advances in our understanding of the LHb circuit organization, yet the precise mechanisms of its involvement in complex behaviors are largely unknown.

Biologically based neural circuit modelling for the study of fear learning and extinction.

The neuronal systems that promote protective defensive behaviours have been studied extensively using Pavlovian conditioning. In this paradigm, an initially neutral-conditioned stimulus is paired with an aversive unconditioned stimulus leading the subjects to display behavioural signs of fear. Decades of research into the neural bases of this simple behavioural paradigm uncovered that the amygdala, a complex structure comprised of several interconnected nuclei, is an essential part of the neural circuits required for the acquisition, consolidation and expression of fear memory.

Erasing fear memories with extinction training.

Decades of behavioral studies have confirmed that extinction does not erase classically conditioned fear memories. For this reason, research efforts have focused on the mechanisms underlying the development of extinction-induced inhibition within fear circuits. However, recent studies in rodents have uncovered mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories.

Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges.

Increasing evidence suggests that disrupted temporal organization impairs behavior, cognition, and affect; further, disruption of circadian clock genes impairs sleep-wake cycle and social rhythms which may be implicated in mental disorders. Despite this strong evidence, a gap in understanding the neural mechanisms of this interaction obscures whether biological rhythms disturbances are the underlying causes or merely symptoms of mental disorder. Here, we review current understanding, emerging concepts, gaps, and opportunities pertinent to (1) the neurobiology of the interactions between circadian oscillators and the neural circuits subserving higher brain function and behaviors of relevance to mental health, (2) the most promising approaches to determine how biological rhythms regulate brain function and behavior under normal and pathological conditions, (3) the gaps and challenges to advancing knowledge on the link between disrupted circadian rhythms/sleep and psychiatric disorders, and (4) the novel strategies for translation of basic science discoveries in circadian biology to clinical settings to define risk, prevent or delay onset of mental illnesses, design diagnostic tools, and propose new therapeutic strategies.

Maternal separation alters drug intake patterns in adulthood in rats.

Maternal separation/handling (MS/H) is an animal model of early life stress that causes profound neurochemical and behavioral alterations in pups that persist into adulthood. Many recent studies have used the MS/H model to study changes in drug effects in adulthood that are linked to behavioral treatments and stressors in the perinatal period. The drug effects focused on in this review are the reinforcing properties of the abused drugs, cocaine and alcohol.

The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction.

CART (cocaine- and amphetamine-regulated transcript) peptides are neuromodulators that are involved in feeding, drug reward, stress, cardiovascular function, and bone remodeling. CART peptides are abundant but discretely distributed in the brain, pituitary and adrenal glands, pancreas, and gut. High expression of CART in discrete hypothalamic nuclei associated with feeding has led to behavioral and pharmacological studies that strongly support an anorectic action of CART in feeding.

The CART receptors: background and recent advances.

Previous evidence obtained from several behavioral and biochemical studies suggested the existence of multiple CART receptors. However, identification of CART receptor binding has been largely unsuccessful until recently. The first evidence of CART signaling properties came from a study demonstrating that CART 55-102 inhibited voltage-dependent intracellular calcium signaling.

CART peptide diurnal variations in blood and brain.

The central role of CART peptide in feeding, drug abuse and stress has been widely researched however, CART's role in the peripheral system are less explored. CART peptide is present in a variety of peripheral tissues including sympathetic ganglion neurons, adrenal glands, gut, pancreas and blood. Studies that examined circulating CART demonstrated that the active fragment with a molecular weight of CART55-102 is present in the blood of rats and rhesus macaques.

Maternal separation alters serotonergic transporter densities and serotonergic 1A receptors in rat brain.

Rationale: The basic mechanisms underlying the association between early life maternal separation and adulthood psychiatric disorders are largely unknown. One possible candidate is the central serotonergic system, which is also abnormal in psychiatric illnesses. Neuroadaptational changes in serotonergic transporter and serotonergic 1A receptors may underlie links between early life stress and adulthood psychiatric disorders.

Regulation of CART mRNA in the rat nucleus accumbens via D3 dopamine receptors.

A variety of studies indicate that CART in the nucleus accumbens (NAcc) is involved in the action of psychostimulants. In order to understand in more detail if and how dopamine is involved in the regulation of CART mRNA in the NAcc, the present studies of individual receptors were performed. The D1 agonist, dihydrexidine, and the D1 antagonist, SCH23,390, were administered separately and in combination to adult male rats; however, no changes were found in CART mRNA as measured by in situ hybridization.

CART (cocaine- and amphetamine-regulated transcript) peptide receptors: specific binding in AtT20 cells.

Given previous evidence for CART (cocaine- and amphetamine-regulated transcript) signaling in AtT20 cells, the binding of [125I]-CART61-102 was characterized in these cells. The binding was specific, saturable, dependent on time, pH, temperature and protein concentration, with a Bmax of 101.4+/-8.

The effects of cocaine on CART expression in the rat nucleus accumbens: a possible role for corticosterone.

CART (Cocaine- and Amphetamine-Regulated Transcript) was initially described as an mRNA which had increased expression in the rat striatum following administration of acute cocaine or amphetamine but not saline. However, not all subsequent studies confirmed this. The present study aimed to repeat experiments with conflicting results and to reexamine and extend the original finding of acute regulation of nucleus accumbens CART mRNA by cocaine.

Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors.

CART peptides are important neurotransmitters, but little is known about their receptors or signaling pathways in cells. In this study we describe the effects of CART 55-102 on the stimulation of extracellular signal-related kinase (ERK) in a pituitary-derived cell line. CART 55-102 treatment resulted in markedly enhanced ERK phosphorylation in AtT20 and GH3 cells, but had no significant effect on ERK phosphorylation levels in a variety of other cell types that were examined.

CART peptide diurnal rhythm in brain and effect of fasting.

We have recently shown that CART peptides exhibit a diurnal rhythm in blood that is affected by food intake and glucocorticoids. In the present study, we extend our observations by demonstrating that CART peptides also exhibit a diurnal rhythm in several brain regions, notably the nucleus accumbens, hypothalamus and amygdala, but not in the midbrain. To examine whether the CART peptide rhythm was dependent on food intake, animals were food-deprived for 24 h.

Effect of corticosterone on CART peptide levels in rat blood.

We have recently demonstrated that CART peptides display a diurnal rhythm in blood that depends partly on glucocorticoids levels. This study extends previous findings by directly testing the effects of acute administration of corticosterone and metyrapone on CART peptide levels in blood. Acute treatment with corticosterone augmented CART levels, while metyrapone administration prevented the increase in CART in the evening hours.

CART peptides: modulators of mesolimbic dopamine, feeding, and stress.

CART peptides have been shown to be peptide neurotransmitters and endocrine factors in a series of cumulative studies over the past eight years or so. This brief review touches on three aspects of CART: CART as a mediator or modulator of mesolimbic dopamine, CART's regulation by glucocorticoids, and CART as a regulator of feeding, satiety, and body weight. There have been several recent reviews and publications on various aspects of CART peptides.

CART in feeding and obesity.

CART (cocaine- and amphetamine-regulated transcript) peptides are neurotransmitters that have received much attention as mediators of feeding behavior and body-weight regulation in mammals. CART peptides and their mRNAs are found in many brain regions and in peripheral tissues that are involved in feeding, and many animal studies implicate CART as an inhibitor of feeding. Animal studies also demonstrate that CART expression is regulated by both leptin and glucocorticoids, two hormones known to be associated with the regulation of body weight.

Cocaine- and amphetamine-regulated transcript peptide levels in blood exhibit a diurnal rhythm: regulation by glucocorticoids.

Cocaine- and amphetamine-regulated transcript (CART) peptides are novel neurotransmitters that are implicated in several physiological functions such as control of feeding behavior, drug reward, sensory processing, stress, and development. Although a majority of studies have examined the role of CART in the brain, less is known about its function in the periphery. Therefore, the goals of this study were to examine the levels and species of CART peptides in blood, to determine whether they undergo diurnal rhythms, and to elucidate their sources and regulatory factors.

CART peptides are modulators of mesolimbic dopamine and psychostimulants.

CART peptide produces behavioral effects when injected into the VTA or nucleus accumbens. In the VTA, the peptide behaves like an endogenous psychostimulant and produces increased locomotor activity and conditioned place preference. Since this is blocked by dopamine receptor blockers, it presumably involves release of dopamine.

Biochemistry and pharmacology of epitope-tagged alpha(1)-adrenergic receptor subtypes.

Human alpha(1A)-, alpha(1B)-, and alpha(1D)-adrenergic receptors were tagged at their amino termini with FLAG epitopes and stably expressed in human embryonic kidney (HEK)293 cells. Tagged receptors demonstrated a wild-type pharmacology and mobilization of intracellular Ca(2+). After solubilization and immunoprecipitation, monomers, dimers, and trimers of each subtype were apparent on Western blots.

Neurotransmitter transporters synthesis and degradation rates.

The synthesis rate, half-life and degradation rate constant of dopamine and serotonin transporter proteins have been determined using RTI-76, an irreversible inhibitor of ligand binding at transporters, and a model assuming that synthesis rate is zero order and degradation rate is a first order process. The half-lives of transporter recovery after inactivation with RTI-76 are approximately 2-3 days, which are similar to those for other synaptic proteins.