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Environmental pollution by pharmaceuticals is increasingly recognized as a major threat to aquatic ecosystems worldwide. A variety of pharmaceuticals enter waterways by way of treated wastewater effluents and remain biochemically active in aquatic systems. Several ecotoxicological studies have been done, but generally, little is known about the ecological effects of pharmaceuticals. Here we show that a benzodiazepine anxiolytic drug (oxazepam) alters behavior and feeding rate of wild European perch (Perca fluviatilis) at concentrations encountered in effluent-influenced surface waters. Individuals exposed to water with dilute drug concentrations (1.8 micrograms liter -1 ) exhibited increased activity, reduced sociality, and higher feeding rate. As such, our results show that anxiolytic drugs in surface waters alter animal behaviors that are known to have ecological and evolutionary consequences.

Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.

Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood–brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood–brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.

The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

Glucagon-like peptide-1 (GLP-1) is produced in the small intestines and in nucleus tractus solitarius (NTS) neurons. Activation of central GLP-1 receptors (GLP-1Rs) reduces feeding and body weight. The neural circuits mediating these effects are only partially understood. Here we investigate the inhibition of food intake and motivated responding for food in rats following GLP-1R activation in the ventral hippocampal formation (HPFv), a region only recently highlighted in food intake control. Increased HPFv GLP-1R activity following exendin-4 administration potently reduced food intake (both chow and Western diet) and body weight, whereas HPFv GLP-1R blockade increased food intake. These hypophagic effects were based on reduced meal size, and likely do not involve nausea as HPFv exendin-4 did not induce a conditioned flavor avoidance. HPFv GLP-1R activation also reduced effort-based responding for food under an operant progressive ratio reinforcement schedule, but did not affect food conditioned place preference expression. To investigate possible routes of HPFv GLP-1 signaling, immunohistochemical analysis revealed the absence of GLP-1 axon terminals in the HPFv, suggesting volume transmission as a mechanism of action. Consistent with this, the presence of active GLP-1 was detected in both the cerebrospinal fluid (CSF) and the HPFv. The source of CSF GLP-1 may be NTS GLP-1-producing neurons, as, (1) ∼30% of NTS GLP-1 neurons colocalized with the retrograde tracer fluorogold (FG) following lateral ventricle FG injection, and (2) GLP-1-immunoreactive axon terminals were observed adjacent to the ventricular ependymal layer. Collectively these findings illuminate novel neuronal and behavioral mechanisms mediating food intake reduction by GLP-1.

Chronic exposure of bumblebees to two pesticides (a neonicotinoid and a pyrethroid) independently and in combination, at concentrations approximating field-level exposure, impairs natural foraging behaviour and increases worker mortality, with knock-on effects for brood development and colony success. Pesticides knock bees off course Exposure to neonicotinoid pesticides is known to influence bee behaviour, and could be a key factor in current bee declines. It has not been possible to establish a mechanistic link between individual and colony effects, but this study demonstrates a direct link between detrimental behavioural effects and field-level pesticide exposure — to neonicotinoid and pyrethroid — in individual worker bumblebees, and consequent impacts on colony development and survival. The pesticides reduce the effectiveness of foraging behaviour, with knock-on effects on brood care and colony productivity. Reported widespread declines of wild and managed insect pollinators have serious consequences for global ecosystem services and agricultural production 1 , 2 , 3 . Bees contribute approximately 80% of insect pollination, so it is important to understand and mitigate the causes of current declines in bee populations 4 , 5 , 6 . Recent studies have implicated the role of pesticides in these declines, as exposure to these chemicals has been associated with changes in bee behaviour 7 , 8 , 9 , 10 , 11 and reductions in colony queen production 12 . However, the key link between changes in individual behaviour and the consequent impact at the colony level has not been shown. Social bee colonies depend on the collective performance of many individual workers. Thus, although field-level pesticide concentrations can have subtle or sublethal effects at the individual level 8 , it is not known whether bee societies can buffer such effects or whether it results in a severe cumulative effect at the colony level. Furthermore, widespread agricultural intensification means that bees are exposed to numerous pesticides when foraging 13 , 14 , 15 , yet the possible combinatorial effects of pesticide exposure have rarely been investigated 16 , 17 . Here we show that chronic exposure of bumblebees to two pesticides (neonicotinoid and pyrethroid) at concentrations that could approximate field-level exposure impairs natural foraging behaviour and increases worker mortality leading to significant reductions in brood development and colony success. We found that worker foraging performance, particularly pollen collecting efficiency, was significantly reduced with observed knock-on effects for forager recruitment, worker losses and overall worker productivity. Moreover, we provide evidence that combinatorial exposure to pesticides increases the propensity of colonies to fail.

Concerns are being raised that microplastic pollution can have detrimental effects on the feeding of aquatic invertebrates, including zooplankton. Both small plastic fragments (microplastics, MPs) produced by degradation of larger plastic waste (secondary MPs; SMPs) and microscopic plastic spheres used in cosmetic products and industry (primary MPs; PMPs) are ubiquitously present in the environment. However, despite the fact that most environmental MPs consist of weathered plastic debris with irregular shape and broad size distribution, experimental studies of organism responses to MP exposure have largely used uniformly sized spherical PMPs. Therefore, effects observed for PMPs in such experiments may not be representative for MP-effects in situ. Moreover, invertebrate filter-feeders are generally well adapted to the presence of refractory material in seston, which questions the potential of MPs at environmentally relevant concentrations to measurably affect digestion in these organisms. Here, we compared responses to MPs (PMPs and SMPs) and naturally occurring particles (kaolin clay) using the cladoceran Daphnia magna as a model organism. We manipulated food levels (0.4 and 9 μg C mL-1) and MP or kaolin contribution to the feeding suspension (<1 to 74%) and evaluated effects of MPs and kaolin on food uptake, growth, reproductive capacity of the daphnids, and maternal effects on offspring survival and feeding. Exposure to SMPs caused elevated mortality, increased inter-brood period and decreased reproduction albeit only at high MP levels in the feeding suspension (74% by particle count). No such effects were observed in either PMP or kaolin treatments. In daphnids exposed to any particle type at the low algal concentration, individual growth decreased by ~15%. By contrast, positive growth response to all particle types was observed at the high algal concentration with 17%, 54% and 40% increase for kaolin, PMP and SMP, respectively. When test particles comprised 22% in the feeding suspension, both MP types decreased food intake by 30%, while kaolin had no effect. Moreover, SMPs were found to homoaggregate in a concentration-dependent manner, which resulted in a 77% decrease of the ingested SMPs compared to PMPs. To better understand MP-processing in the gut, gut passage time (GPT) and evacuation rate of MPs were also assayed. SMPs and PMPs differed in their effects on daphnids; moreover, the particle effects were dependent on the MP: algae ratio in the suspension. When the MP contribution to the particle abundance in the medium changed from 1 to 4%, GPT for daphnids exposed to SMPs increased 2-fold. Our results suggest that MPs and, in particular, SMPs, have a greater capacity to negatively affect feeding in D. magna compared to naturally occurring mineral particles of similar size. Moreover, grazer responses observed in experiments with PMPs cannot be extrapolated to the field where SMPs dominate, because of the greater effects caused by the latter.

It is well recognized that ventromedial hypothalamus (VMH) serves as a satiety center in the brain. However, the feeding circuit for the VMH regulation of food intake remains to be defined. Here, we combine fiber photometry, chemo/optogenetics, virus-assisted retrograde tracing, ChR2-assisted circuit mapping and behavioral assays to show that selective activation of VMH neurons expressing steroidogenic factor 1 (SF1) rapidly inhibits food intake, VMH SF1 neurons project dense fibers to the paraventricular thalamus (PVT), selective chemo/optogenetic stimulation of the PVT-projecting SF1 neurons or their projections to the PVT inhibits food intake, and chemical genetic inactivation of PVT neurons diminishes SF1 neural inhibition of feeding. We also find that activation of SF1 neurons or their projections to the PVT elicits a flavor aversive effect, and selective optogenetic stimulation of ChR2-expressing SF1 projections to the PVT elicits direct excitatory postsynaptic currents. Together, our data reveal a neural circuit from VMH to PVT that inhibits food intake. The ventromedial hypothalamus (VMH) serves as a satiety center in the brain, however, the neural circuits involved are incompletely understood. Here, the authors decipher a neural circuit from VMH to the paraventricular thalamus that suppresses food intake.

Melanocortin 4 receptors (MC4Rs) are critical to the promotion of homeostatic satiety. The authors established paraventricular hypothalamus (PVH) MC4R-expressing neurons as a functional target for orexigenic arcuate nucleus agouti-related peptide–expressing neurons and identify an explicit PVH MC4R-expressing neuron to lateral parabrachial nucleus satiety-promoting circuit, the activation of which encodes positive valence in calorically depleted mice. Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH MC4R neurons and further identify these cells as a functional exponent of ARC AgRP neuron–driven hunger. Moreover, we reveal this function to be mediated by a PVH MC4R →lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH MC4R →LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.

This study shows that activation of cannabinoid type-1 (CB1) receptors in the olfactory bulb increases odor detection and food intake in hungry mice. The authors show that this function is mediated by CB1-dependent attenuation of excitatory corticofugal synaptic transmission onto inhibitory granule cells and disinhibition of mitral cells in the main olfactory bulb. Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB 1 ) receptors promote food intake in fasted mice by increasing odor detection. CB 1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB 1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB 1 receptor–dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.