Pituitary Adenylate Cyclase-Activation Polypeptide (PACAP) Regulates Feeding in the Rat Striatum and Hypothalamus

The following dissertation focuses on preclinical rodent feeding paradigms that were designed to examine the mechanisms by which the brain regulates caloric (homeostatic) and palatability (hedonic)-driven feeding. Taken together, my findings suggest differentially motivated feeding can, in part, signal through isolated non-overlapping mechanisms in the brain. Furthermore, some of these mechanisms occur in similar neurocircuits that have been implicated in other compulsive behaviors, such as drug abuse. In an effort to support the argument that binge eating disorder (BED) and substance abuse share similar behavioral and molecular targets, we first demonstrate that the development of BED in rodents is attenuated by both systemic and central administration of a cysteine pro-drug (N-acetylcysteine or NAC) which is a compound that targets the understudied glutamate system and is currently used to treat other disorders that have aspects of compulsion, such as trichotillomania or drug addiction (chapter II). Interestingly, NAC-induced hypophagia is specific to feeding stimulated by palatability as NAC did not produce any suppression of feeding in animals not maintained under a feeding paradigm that would produce binge behavior. In addition to studying differentially motivated feeding, a large component of this dissertation examines the mechanisms by which the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates feeding in the ventromedial nucleus of the hypothalamus (VMN) as well as the nucleus accumbens (NAc). Our results indicate that PACAP microinjected into the VMN suppresses feeding elicited specifically by food deprivation, as PACAP did not effecting feeding elicited by palatability. Interestingly, in the nucleus accumbens, a brain region important for reward related activity, PACAP suppresses palatably-driven feeding in satiated rats, while not effecting feeding driven by food deprivation (chapter III). The opposing behavioral effects of PACAP on feeding propelled the lab to further investigate the mechanism by which PACAP was working in these two regions. In the VMN, we demonstrate that PACAP interacts with leptin signaling as acute blockade of PACAP receptors (PAC1R) in the VMN inhibits the behavioral and molecular actions of leptin (chapter IV). In the nucleus accumbens, PACAP attenuates hedonic drive in a site-specific manner and we identified PACAP mRNA expressing striatal afferents originating in the prefrontal cortex (chapter V), which is significant as obese individuals display hypoactive medial prefrontal cortex and stimulation of this area decreases calories consumed and body weight. Taken together, the opposing behavioral effects of PACAP emphasize an important point that a signaling mechanism in one brain region can be significantly different in another

Organic Cation Transporter 3 (OCT3) Is Localized to Intracellular and Surface Membranes in Select Glial and Neuronal Cells Within the Basolateral Amygdaloid Complex of Both Rats and Mice

Organic cation transporter 3 (OCT3) is a high-capacity, low-affinity transporter that mediates corticosterone-sensitive uptake of monoamines including norepinephrine, epinephrine, dopamine, histamine and serotonin. OCT3 is expressed widely throughout the amygdaloid complex and other brain regions where monoamines are key regulators of emotional behaviors affected by stress. However, assessing the contribution of OCT3 to the regulation of monoaminergic neurotransmission and monoamine-dependent regulation of behavior requires fundamental information about the subcellular distribution of OCT3 expression. We used immunofluorescence and immuno-electron microscopy to examine the cellular and subcellular distribution of the transporter in the basolateral amygdaloid complex of the rat and mouse brain. OCT3-immunoreactivity was observed in both glial and neuronal perikarya in both rat and mouse amygdala. Electron microscopic immunolabeling revealed plasma membrane-associated OCT3 immunoreactivity on axonal, dendritic, and astrocytic processes adjacent to a variety of synapses, as well as on neuronal somata. In addition to plasma membrane sites, OCT3 immunolabeling was also observed associated with neuronal and glial endomembranes, including Golgi, mitochondrial and nuclear membranes. Particularly prominent labeling of the outer nuclear membrane was observed in neuronal, astrocytic, microglial and endothelial perikarya. The localization of OCT3 to neuronal and glial plasma membranes adjacent to synaptic sites is consistent with an important role for this transporter in regulating the amplitude, duration, and physical spread of released monoamines, while its localization to mitochondrial and outer nuclear membranes suggests previously undescribed roles for the transporter in the intracellular disposition of monoamines

Furnishing the Galaxy with Pulsars

The majority of pulsar population synthesis studies performed to date have focused on isolated pulsar evolution. Those that have incorporated pulsar evolution within binary systems have tended to either treat binary evolution poorly of evolve the pulsar population in an ad-hoc manner. Here we present the first model of the Galactic field pulsar population that includes a comprehensive treatment of both binary and pulsar evolution. Synthetic observational surveys mimicking a variety of radio telescopes are then performed on this population. As such, a complete and direct comparison of model data with observations of the pulsar population within the Galactic disk is now possible. The tool used for completing this work is a code comprised of three components: stellar/binary evolution, Galactic kinematics and survey selection effects. Here we give a brief overview of the method and assumptions involved with each component. Some preliminary results are also presented as well as plans for future applications of the code.Comment: 3 pages, 3 figures, Conference: "40 years of pulsars: Millisecond pulsars, magnetars and more", McGill University, Montreal, Canada, ed. A.Cumming et al., AI

Gateway earth taking off: Detailing infrastructure and mission logistics

Gateway Earth Development Group is an international think-tank proposing new modular space access architecture, centred on operating a combined research space station and commercial space hotel in the geostationary orbit (GEO) – the Gateway Earth complex. At this location, robotic and crewed interplanetary spacecraft could be assembled, including through utilising in-situ (additive) manufactured components, and dock before they travel to, and return from, any Solar System destination. Moreover, space tourism and GEO satellite maintenance could provide a significant part of the funding to build and maintain the complex. Our current work is related to creating a detailed infrastructure development and mission operation programme, with particular focus on incorporating new technologies (such as electric propulsion, and inflatable/configurable habitats) and innovative efficiencies (re-usability and re-deployment of access vehicles and on-orbit assets). Specifically, a detailed deployment analysis is being undertaken as well as further valorisation of the complex market opportunity. In this paper we will present the current state of play in our proposal and solicit comments as to further improvements

Expression Patterns of BDNF with Central Anorexigenic Signaling Pathways Involving PACAP in the Hypothalamic Ventromedial Nuclei

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid polypeptide belonging to the secretin super family of peptides. PACAP binds to its type 1 receptor (PAC1R) with greater affinity than for the receptors for vasoactive intestinal polypeptides (VIP), VPAC1 and VPAC2. Although mRNA for PACAP and its receptor PAC1R are found throughout the central nervous system, they are abundantly expressed in the hypothalamic ventromedial nuclei (VMN). In male Sprague Dawley rats, infusions of PACAP into the VMN produce a robust decrease in food intake with concomitant increased energy expenditure, decreased body weight, and significantly elevated brain-derived neurotrophic factor (BDNF) mRNA expression in the VMN. This latter effect of PACAP on BDNF mRNA expression has been shown to occur in other brain regions. Exogenous BDNF in the VMN regulates energy homeostasis in a manner similar to that of PACAP with decreased feeding and increased metabolism. Although the physiological responses to individual PACAP and BDNF infusions in the VMN lead to decreased feeding behavior and body weight loss, the anatomical distribution of these two cell signals in the VMN has not been established. PACAP-induced changes in BDNF mRNA expression in the VMN may reveal an important interaction with PACAP signaling in the control of feeding behavior. In the present study, we have employed double-labeled fluorescent in-situ hybridization (FISH) to examine the expression patterns of PACAP, PAC1R and BDNF mRNA containing neuronal cells. In the VMN, PACAP mRNA expressing cells co-express BDNF, PAC1R, and VGLUT2. BDNF mRNA expressing cells co-express PAC1R and PACAP. Coupled with previous behavioral data demonstrating PACAP- and BDNF-induced changes in feeding behavior, the co-expression of BDNF with PACAP and PAC1R mRNA in the VMN suggest a potential functional relationship between the two signaling peptides in the regulation of energy homeostasis. The specific and integrated contributions of PACAP and BDNF in the VMN towards regulating energy homeostasis and feeding behavior still remain to be studied

Measurement Properties of the Motivation for Youth Treatment Scale with a Residential Group Home Population

A client’s motivation to receive services has long been identified as a highly relevant component of mental health treatment. In fact, ample evidence demonstrates that client motivation is significantly related to seeking services, remaining in services, and improved client outcomes (e.g., Broome, Joe, & Simpson, 2001; Ryan, Plant, & O’Malley, 1995; Schroder, Sellman, Frampton, & Deering, 2009). Additionally, it has been recognized that motivation is a “dynamic” characteristic that changes throughout treatment (Melnick, De Leon, Hawke, Jainchill, & Kressel, 1997; Schroder et al., 2009). In this way, motivation is an important client factor to assess and monitor throughout the treatment process. The broad construct of motivation is comprised of two separate, but related components conceptualized as motivation to change and motivation for treatment. As defined by DiClamente, Schlundt, and Gemmell (2004), motivation to change refers to a willingness to recognize problematic behavior and take steps toward change, whereas motivation for treatment refers to a willingness to seek help and remain compliant with an intervention program. In other words, a motivated person not only perceives the importance of changing, but also has confidence that they are able to be successful at making the change (Burke, Arkowitz, & Menchola, 2003)

Rate of improvement of CF life expectancy exceeds that of general population: observational death registration study

Background: It is unclear why cystic fibrosis (CF) survival has improved. We wished to quantify increases in CF median age of death in the context of general population survival improvement. Method: Death registration data analysis (US, England & Wales (E&W)—1972–2009). Results: CF median age of death is higher in US than E&W and greater for males, opposite to that of death from all causes. CF median age of death has increased by 0.543 life years per year (E&W, US combined (95% confidence interval 0.506, 0.582)). The difference in median age at death between those dying from all causes and CF decreased in both territories. CF median age of death for males is greater than for females in both territories. This gap has not narrowed. Conclusion: The median age of death of people with CF is improving more rapidly than that of the general population in US and E&W

Pituitary Adenylate-Cyclase Activating Polypeptide Regulates Hunger- and Palatability-Induced Binge Eating

While pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the hypothalamic ventromedial nuclei (VMN) has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger) and hedonic-related (palatability) drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding); surprisingly, this manipulation failed to alter palatable food consumption in satiated rats (e.g., hedonic feeding). In contrast, inhibition of the nucleus accumbens (NAc), through local microinjections of GABA receptor agonists baclofen and muscimol, decreased hedonic feeding without altering homeostatic feeding. PACAP microinjections produced the site-specific changes in synaptic transmission needed to decrease feeding via VMN or NAc circuitry. PACAP into the NAc mimicked the actions of GABA agonists by reducing hedonic feeding without altering homeostatic feeding. In contrast, PACAP into the VMN mimicked the actions of AMPA by decreasing homeostatic feeding without affecting hedonic feeding. Slice electrophysiology recordings verified PACAP excitation of VMN neurons and inhibition of NAc neurons. These data suggest that the VMN and NAc regulate distinct circuits giving rise to unique feeding drives, but that both can be regulated by the neuropeptide PACAP to potentially curb excessive eating stemming from either drive