Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation.

The orexin (also known as hypocretin) system, consisting of neuropeptides orexin-A and orexin-B, was discovered over 25 years ago and was immediately identified as a central regulator of sleep and wakefulness. These peptides interact with two G-protein coupled receptors, orexin 1 (OX) and orexin 2 (OX) receptors which are capable of coupling to all heterotrimeric G-protein subfamilies, but primarily transduce increases in calcium signalling. Orexin neurons are regulated by a variety of transmitter systems and environmental stimuli that signal reward availability, including food and drug related cues.

Distinct Neuromodulatory Effects of Endogenous Orexin and Dynorphin Corelease on Projection-Defined Ventral Tegmental Dopamine Neurons.

Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues, and circuit-specific signaling drives different aspects of motivated behavior. Orexin (ox; also known as hypocretin) and dynorphin (dyn) are coexpressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors.

Obesity- and diet-induced plasticity in systems that control eating and energy balance.

In April 2023, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in partnership with the National Institute of Child Health and Human Development, the National Institute on Aging, and the Office of Behavioral and Social Sciences Research, hosted a 2-day online workshop to discuss neural plasticity in energy homeostasis and obesity. The goal was to provide a broad view of current knowledge while identifying research questions and challenges regarding neural systems that control food intake and energy balance. This review includes highlights from the meeting and is intended both to introduce unfamiliar audiences with concepts central to energy homeostasis, feeding, and obesity and to highlight up-and-coming research in these areas that may be of special interest to those with a background in these fields.

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology.

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX and OX Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia.

Characterization of dopaminergic projections from the ventral tegmental area and the dorsal raphe nucleus to the orbital frontal cortex.

The orbitofrontal cortex (OFC) is a key node in the cortico-limbic-striatal circuitry that influences decision-making guided by the relative value of outcomes. Midbrain dopamine from either the ventral tegmental area (VTA) or the dorsal raphe nucleus (DRN) has the potential to modulate OFC neurons; however, it is unknown at what concentrations these terminals release dopamine. Male and female adult dopamine transporter (DAT)-tdTomato mice were injected with AAV2/8-EF1a-DIO-eYFP into either the DRN or the VTA or the retrograde label cholera toxin B (CTB) 488 in the medial or lateral OFC.

Short- and Long-Term High-Fat Diet Exposure Differentially Alters Phasic and Tonic GABAergic Signaling onto Lateral Orbitofrontal Pyramidal Neurons.

The chronic consumption of caloric dense high-fat foods is a major contributor to increased body weight, obesity, and other chronic health conditions. The orbitofrontal cortex (OFC) is critical in guiding decisions about food intake and is altered with diet-induced obesity. Obese rodents have altered morphologic and synaptic electrophysiological properties in the lateral orbitofrontal cortex (lOFC).

Sex Differences in Plasma, Adipose Tissue, and Central Accumulation of Cannabinoids, and Behavioral Effects of Oral Cannabis Consumption in Male and Female C57BL/6 Mice.

Background: Cannabis edibles are an increasingly popular form of cannabis consumption. Oral consumption of cannabis has distinct physiological and behavioral effects compared with injection or inhalation. An animal model is needed to understand the pharmacokinetics and physiological effects of oral cannabis consumption in rodents as a model for human cannabis edible use.

Impact of insulin and insulin resistance on brain dopamine signalling and reward processing - An underexplored mechanism in the pathophysiology of depression?

Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour.

Disinhibition of the orbitofrontal cortex biases decision-making in obesity.

The lateral orbitofrontal cortex (lOFC) receives sensory information about food and integrates these signals with expected outcomes to guide future actions, and thus may play a key role in a distributed network of neural circuits that regulate feeding behavior. Here, we reveal a new role for the lOFC in the cognitive control of behavior in obesity. Food-seeking behavior is biased in obesity such that in male obese mice, behaviors are less flexible to changes in the perceived value of the outcome.

Development of an Open Face Home Cage Running Wheel for Testing Activity-Based Anorexia and Other Applications.

Running wheels for mice residing in the home cage are useful for the continuous measurement of locomotor activity for studies testing exercise interventions or exercise-induced effects on brain and metabolism. Here, we have developed an open source, printable, open-faced running wheel that is automated to collect locomotor information such as distance traveled, wheel direction, and velocity that can be binned into epochs over 24 h or multiple days. This system allows for remote data collection to avoid human interference in mouse behavioral experiments.

Food for thought: diet-induced impairments to decision-making and amelioration by N-acetylcysteine in male rats.

Rationale: Attempts to lose weight often fail despite knowledge of the health risks associated with obesity and determined efforts. We previously showed that rodents fed an obesogenic diet displayed premature habitual behavioural control and weakened flexible decision-making based on the current value of outcomes produced by their behaviour. Thus, habitual control may contribute to failed attempts to modify eating behaviours.

Activation of LH GABAergic inputs counteracts fasting-induced changes in tVTA/RMTG neurons.

Dopamine neurons in the ventral tegmental area (VTA) are strongly innervated by GABAergic neurons in the 'tail of the VTA' (tVTA), also known as the rostralmedial tegmental nucleus (RMTg). Disinhibition of dopamine neurons through firing of the GABAergic neurons projecting from the lateral hypothalamus (LH) leads to reward seeking and consumption through dopamine release in the nucleus accumbens. VTA dopamine neurons respond to changes in motivational state, yet less is known about whether tVTA/RMTg GABAergic neurons or the LH GABAergic neurons that project to them are also affected by changes in motivational state, such as fasting.

Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist.

Human trace amine-associated receptor subtype 1 (hTAAR1) is a G protein-coupled receptor that has therapeutic potential for multiple diseases, including schizophrenia, drug addiction, and Parkinson's disease (PD). Although several potent agonists have been identified and have shown positive results in various clinical trials for schizophrenia, the discovery of potent hTAAR1 antagonists remains elusive. Herein, we report the results of structure-activity relationship studies that have led to the discovery of a potent hTAAR1 antagonist (RTI-7470-44, ).

Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats.

Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis).

Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours.

Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin.

Prebiotic, Probiotic, and Synbiotic Consumption Alter Behavioral Variables and Intestinal Permeability and Microbiota in BTBR Mice.

Given that prebiotics have been shown to improve gut microbiota composition, gastrointestinal symptoms and select behaviors in autism spectrum disorder (ASD), we hypothesized that prebiotic supplementation would improve sociability, communication, and repetitive behaviors in a murine model of ASD. We also examined the effect of a synbiotic (probiotic + prebiotic). Juvenile male BTBR mice were randomized to: (1) control; (2) probiotic (1 × 10 CFU/d RC-14; now known as ); (3) prebiotic (10% oligofructose-enriched inulin); (4) prebiotic + probiotic (n = 12/group) administered through food for 3 weeks.

Obesity-induced astrocyte dysfunction impairs heterosynaptic plasticity in the orbitofrontal cortex.

Overconsumption of highly palatable, energy-dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here, we show that extended access to a cafeteria diet impairs astrocyte glutamate clearance, which leads to a heterosynaptic depression of GABA transmission onto pyramidal neurons of the OFC.

Insulin and endocannabinoids in the mesolimbic system.

Easy access to palatable food and an abundance of food-related cues exacerbate non-homeostatic feeding. The metabolic and economical sequelae of non-homeostatic feeding outweigh those of homeostatic feeding and contribute significantly to the global obesity pandemic. The mesolimbic dopamine system is the primary central circuit that governs the motivation to consume food.

Corticosterone Attenuates Reward-Seeking Behavior and Increases Anxiety via D2 Receptor Signaling in Ventral Tegmental Area Dopamine Neurons.

Corticosteroids (CORT) have been widely used in anti-inflammatory medication. Chronic CORT treatment can cause mesocorticolimbic system dysfunctions, which are known to play a key role for the development of psychiatric disorders. The VTA is a critical site in the mesocorticolimbic pathway and is responsible for motivation and reward-seeking behaviors.

Cellular and behavioral basis of cannabinioid and opioid interactions: Implications for opioid dependence and withdrawal.

The brain's endogenous opioid and endocannabinoid systems are neuromodulatory of synaptic transmission, and play key roles in pain, memory, reward, and addiction. Recent clinical and pre-clinical evidence suggests that opioid use may be reduced with cannabinoid intake. This suggests the presence of a functional interaction between these two systems.