The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms

An open-source, automated home-cage sipper device for monitoring liquid ingestive behavior in rodents

Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput experiments; and (4) it is open source so that others can modify it to fit their experimental needs. We validated the performance of this device in three experiments. First, we calibrated our device using time-lapse video-based measurements of liquid intake and correlated sipper interactions with liquid intake. Second, we used the sipper device to measure preference for water versus chocolate milk, demonstrating its utility for two-bottle choice tasks. Third, we integrated the device with fiber photometry, establishing its utility for measuring neural activity in studies of ingestive behavior. This device requires no special equipment or caging, and is small, battery powered, and wireless, allowing it to be placed directly in rodent home cages. The total cost of fabrication is less than $100, and all design files and code are open source. Together, these factors greatly increase scalability and utility for a variety of behavioral neuroscience applications

An open-source, automated home-cage sipper device for monitoring liquid ingestive behavior in rodents

Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput experiments; and (4) it is open source so that others can modify it to fit their experimental needs. We validated the performance of this device in three experiments. First, we calibrated our device using time-lapse video-based measurements of liquid intake and correlated sipper interactions with liquid intake. Second, we used the sipper device to measure preference for water versus chocolate milk, demonstrating its utility for two-bottle choice tasks. Third, we integrated the device with fiber photometry, establishing its utility for measuring neural activity in studies of ingestive behavior. This device requires no special equipment or caging, and is small, battery powered, and wireless, allowing it to be placed directly in rodent home cages. The total cost of fabrication is less than $100, and all design files and code are open source. Together, these factors greatly increase scalability and utility for a variety of behavioral neuroscience applications

The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms

Continuous representations of speed by striatal medium spiny neurons

The striatum is critical for controlling motor output. However, it remains unclear how striatal output neurons encode and facilitate movement. A prominent theory suggests that striatal units encode movements in bursts of activity near specific events, such as the start or end of actions. These bursts are theorized to gate or permit specific motor actions, thereby encoding and facilitating complex sequences of actions. An alternative theory has suggested that striatal neurons encode continuous changes in sensory or motor information with graded changes in firing rate. Supporting this theory, many striatal neurons exhibit such graded changes without bursting near specific actions. Here, we evaluated these two theories in the same recordings of mice (both male and female). We recorded single-unit and multiunit activity from the dorsomedial striatum of mice as they spontaneously explored an arena. We observed both types of encoding, although continuous encoding was more prevalent than bursting near movement initiation or termination. The majority of recorded units did not exhibit positive linear relationships with speed but instead exhibited nonlinear relationships that peaked at a range of locomotor speeds. Bulk calcium recordings of identified direct and indirect pathway neurons revealed similar speed tuning profiles, indicating that the heterogeneity in response profiles was not due to this genetic distinction. We conclude that continuous encoding of speed is a central component of movement encoding in the striatum

An open-source device for measuring food intake and operant behavior in rodent home-cages

Feeding is critical for survival, and disruption in the mechanisms that govern food intake underlies disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: the Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of feeding behavior with minimal experimenter intervention. It has a programmable output for synchronizing behavior with optogenetic stimulation or neural recordings. Finally, FED3 design files are open-source and freely available, allowing researchers to modify FED3 to suit their needs

Deep brain stimulation of the subthalamic nucleus modulates reward-related behavior: A systematic review

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for the motor symptoms of movement disorders including Parkinson\u27s Disease (PD). Despite its therapeutic benefits, STN-DBS has been associated with adverse effects on mood and cognition. Specifically, apathy, which is defined as a loss of motivation, has been reported to emerge or to worsen following STN-DBS. However, it is often challenging to disentangle the effects of STN-DB

VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems

The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to dopamine (DA) neurons, the VTA also contains approximately 30% γ-aminobutyric acid (GABA) neurons. The task of signaling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs), a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioral level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs) to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions

Orbitofrontal-striatal potentiation underlies cocaine-induced hyperactivity

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion but their effects on striatal pathways in vivo remain unclear. The authors show that cocaine increases the activity of direct and indirect pathway striatal neurons of awake mice via the orbitofrontal cortex