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Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time - a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.

The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used snRNA-seq and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding the structure and function of the VP and identified key neuropeptides, neurotransmitters, and neuro receptors that could be targeted within specific VP cell types for functional investigations., Teaser: Genetic identity of ventral pallidum cell types is conserved across rodents and primates at the transcriptional level.

CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function and can be combined with genetically encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific editing across the nervous system. Expressing Cre-dependent Cas9 from a genomic locus affords space to package guide RNAs for gene editing together with Cre-dependent, genetically encoded tools to manipulate, map, or monitor neurons using a single virus. We validated this strategy with three common tools in neuroscience: ChRonos, a channelrhodopsin, for studying synaptic transmission using optogenetics, GCaMP8f for recording Ca 2+ transients using photometry, and mCherry for tracing axonal projections. We tested these tools in multiple brain regions and cell types, including GABAergic neurons in the nucleus accumbens, glutamatergic neurons projecting from the ventral pallidum to the lateral habenula, dopaminergic neurons in the ventral tegmental area, and proprioceptive neurons in the periphery. This flexible approach could help identify and test the function of novel genes affecting synaptic transmission, circuit activity, or morphology with a single viral injection., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Moffa et al.)

Abstract: Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here, we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance conflict, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Furthermore, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury state and significantly correlates with mechanical thresholds. Together, these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays-even when individual inferential statistics do not demonstrate significant mean differences., (Copyright © 2023 International Association for the Study of Pain.)

The striatal and pallidal complexes are basal ganglia structures that orchestrate learning and execution of flexible behavior. Models of how the basal ganglia subserve these functions have evolved considerably, and the advent of optogenetic and molecular tools has shed light on the heterogeneity of subcircuits within these pathways. However, a synthesis of how molecularly diverse neurons integrate into existing models of basal ganglia function is lacking. Here, we provide an overview of the neurochemical and molecular diversity of striatal and pallidal neurons and synthesize recent circuit connectivity studies in rodents that takes this diversity into account. We also highlight anatomical organizational principles that distinguish the dorsal and ventral basal ganglia pathways in rodents. Future work integrating the molecular and anatomical properties of striatal and pallidal subpopulations may resolve controversies regarding basal ganglia network function., (© 2023. Springer Nature America, Inc.)

In this issue of Cell Reports Methods, Dedek et al. present RAMalgo-an AI-powered, automated platform for quantifying nociceptive behaviors in mice. With integrated video tracking and mechanical, thermal, and optogenetic stimulation, RAMalgo has the potential to increase standardization and throughput of pain behavior measurement in rodents., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The ventral tegmental area (VTA) has a pivotal role in motivated behavior. Much of the research on the VTA has focused on the mesocorticolimbic dopamine projections and their role in the computation of a 'reward prediction error' (RPE) for reward-guided learning. In a recent study, Zhou et al. report that VTA GABA neurons, the axons of which innervate the ventral pallidum (VP), have a unique role in signaling reward value to the basal ganglia and guiding reward seeking., Competing Interests: Declaration of interests The authors declare no conflicts of interest in relation to this work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals., Methods: Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking., Results: We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D 1 receptor-expressing NAc spiny projection neurons (NAc D1 SPNs ) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D 2 receptor-expressing neurons (D2 SPNs ). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1 SPNs were enhanced in obese mice relative to lean mice, and these measures were selective for D1 SPNs . Finally, blocking synaptic transmission from D1 SPNs , but not D2 SPNs , in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet-induced weight gain., Conclusions: These experiments demonstrate the necessity of NAc core D1 SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Use of prescription opioids, particularly oxycodone, is an initiating factor driving the current opioid epidemic. There are several challenges with modelling oxycodone abuse. First, prescription opioids including oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl, which have been more commonly used in rodent research. This oral route of administration determines the pharmacokinetic profile, which then influences the establishment of drug-reinforcement associations in animals. Moreover, the pattern of intake and the environment in which addictive drugs are self-administered are critical determinants of the levels of drug intake, of behavioural sensitization and of propensity to relapse behaviour. These are all important considerations when modelling prescription opioid use, which is characterized by continuous drug access in familiar environments. Thus, to model features of prescription opioid use and the transition to abuse, we designed an oral, homecage-based oxycodone self-administration paradigm. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and the majority exhibit preference for oxycodone, escalation of intake, physical signs of dependence and reinstatement of seeking after withdrawal. In addition, a subset of animals demonstrate drug taking that is resistant to aversive consequences. This model is therefore translationally relevant and useful for studying the neurobiological substrates of prescription opioid abuse., (© 2022 Society for the Study of Addiction.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lubejko, Graham, Livrizzi, Schaefer, Banghart and Creed.)

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression-major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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., Competing Interests: BM, TE, MA, EC, JW, AS, AL, KB, LM, MN, YC, KN, EL, AR, RC, RS, SC, RA, JM, MC, VC, MB, MK, ZA, AK No competing interests declared, FC Director of Open Ephys Production Site

The nucleus accumbens shell (NAcSh) and the ventral pallidum (VP) are critical for reward processing, although the question of how coordinated activity within these nuclei orchestrates reward valuation and consumption remains unclear. Inhibition of NAcSh firing is necessary for reward consumption, but the source of this inhibition remains unknown. Here, we report that a subpopulation of VP neurons, the ventral arkypallidal (vArky) neurons, project back to the NAcSh, where they inhibit NAcSh neurons in vivo in mice. Consistent with this pathway driving reward consumption via inhibition of the NAcSh, calcium activity of vArky neurons scaled with reward palatability (which was dissociable from reward seeking) and predicted the subsequent drinking behavior during a free-access paradigm. Activation of the VP-NAcSh pathway increased ongoing reward consumption while amplifying hedonic reactions to reward. These results establish a pivotal role for vArky neurons in the promotion of reward consumption through modulation of NAcSh firing in a value-dependent manner.

Optogenetic tools allow for the selective activation, inhibition or modulation of genetically-defined neural circuits with incredible temporal precision. Over the past decade, application of these tools in preclinical models of psychiatric disease has advanced our understanding the neural circuit basis of maladaptive behaviors in these disorders. Despite their power as an investigational tool, optogenetics cannot yet be applied in the clinical for the treatment of neurological and psychiatric disorders. To date, deep brain stimulation (DBS) is the only clinical treatment that can be used to achieve circuit-specific neuromodulation in the context of psychiatric. Despite its increasing clinical indications, the mechanisms underlying the therapeutic effects of DBS for psychiatric disorders are poorly understood, which makes optimization difficult. We discuss the variety of optogenetic tools available for preclinical research, and how these tools have been leveraged to reverse-engineer the mechanisms underlying DBS for movement and compulsive disorders. We review studies that have used optogenetics to induce plasticity within defined basal ganglia circuits, to alter neural circuit function and evaluate the corresponding effects on motor and compulsive behaviors. While not immediately applicable to patient populations, the translational power of optogenetics is in inspiring novel DBS protocols by providing a rationale for targeting defined neural circuits to ameliorate specific behavioral symptoms, and by establishing optimal stimulation paradigms that could selectively compensate for pathological synaptic plasticity within these defined neural circuits., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch-clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.

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. SIGNIFICANCE STATEMENT The striatum is a structure that is linked to volitional movements and is a primary site of pathology in movement disorders. It remains unclear how striatal neurons encode motor parameters and use them to facilitate movement. Here, we evaluated two models for this: a "discrete encoding model" in which striatal neurons facilitate movements with brief burst of activity near the start and end of movements, and a "continuous encoding model," in which striatal neurons encode the sensory or motor state of the animal with continuous changes in firing. We found evidence primarily in support of the continuous encoding model. This may have implications for understanding the striatal control of movement, as well as informing therapeutic approaches for treating movement disorders., (Copyright © 2020 the authors.)

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., (Copyright © 2019 Godynyuk et al.)

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed., (Copyright © 2019 Ramirez-Zamora, Giordano, Boyden, Gradinaru, Gunduz, Starr, Sheth, McIntyre, Fox, Vitek, Vedam-Mai, Akbar, Almeida, Bronte-Stewart, Mayberg, Pouratian, Gittis, Singer, Creed, Lazaro-Munoz, Richardson, Rossi, Cendejas-Zaragoza, D’Haese, Chiong, Gilron, Chizeck, Ko, Baker, Wagenaar, Harel, Deeb, Foote and Okun.)

The direct and indirect pathway striatal medium spiny neurons (dMSNs and iMSNs) have long been linked to action selection, but the precise roles of these neurons in this process remain unclear. Here, we review different models of striatal pathway function, focusing on the classic "go/no-go" model which posits that dMSNs facilitate movement while iMSNs inhibit movement, and the "complementary" model, which argues that dMSNs facilitate the selection of specific actions while iMSNs inhibit potentially conflicting actions. We discuss the merits and shortcomings of these models and propose a "competitive" model to explain the contribution of these two pathways to behavior. The "competitive" model argues that rather than inhibiting conflicting actions, iMSNs are tuned to the same actions that dMSNs facilitate, and the two populations "compete" to determine the animal's behavioral response. This model provides a theoretical explanation for how these pathways work together to select actions. In addition, it provides a link between action selection and behavioral reinforcement, via modulating synaptic strength at inputs onto dMSNs and iMSNs. Finally, this model makes predictions about how imbalances in the activity of these pathways may underlie behavioral traits associated with psychiatric disorders. Understanding the roles of these striatal pathways in action selection may help to clarify the neuronal mechanisms of decision-making under normal and pathological conditions., (Published by Elsevier B.V.)

Responding to aversive and rewarding stimuli is essential to survival. The ventral pallidum (VP) is a critical node in the mesolimbic network, being the primary output of the nucleus accumbens and projecting to the lateral habenula (LHb) and ventral tegmental area (VTA). The VP is thus poised to modulate the habenula-tegmental circuitry and contribute to processing both rewarding and aversive stimuli. Here, we integrate human functional imaging, behavioral pharmacology in rodents, and recent optogenetic circuit dissection studies of the VP with a focus on the role of the neurochemically-distinct subpopulations in aversion processing. These recent results support a model in which glutamatergic VP neurons play a unique role in aversion processing, while canonical GABAergic VP neurons promote reinforcement and encode the hedonic value of reward. Genetic ablation of glutamatergic, but not GABAergic VP neurons abolishes devaluation of natural reward (sucrose) by pairing with an aversive stimulus (lithium chloride injection). Both of these populations modulate activity throughout the LHb and VTA, which is necessary for expression of adaptive behavior in response to rewarding or aversive stimuli. Future work will address how neuromodulators such as endogenous opioids or dopamine shape function and plasticity within these distinct populations of VP neurons, when these subpopulations are engaged during learning responses to rewarding and aversive stimuli, and how their activity is altered in models of reward-related disorders. Answering these questions will be necessary to understand the basis and ultimately develop targeted therapies for disorders of reward/aversion processing, such as affective, chronic pain and substance use disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity 1,2 and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here we show that high-frequency activity induces LTP at hippocampus-NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. We conclude that hippocampus-NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Background: The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking., Methods: Using neurochemical, genetic, and electrophysiological approaches, we characterized glutamatergic VP neurons (n = 4-8 mice/group). We performed patch clamp and in vivo electrophysiology recordings in the lateral habenula, rostromedial tegmental nucleus, and ventral tegmental area to determine the effect of glutamatergic VP neuron activation in these target regions (n = 6-10 mice/group). Finally, we selectively optogenetically stimulated glutamatergic VP neurons in a real-time place preference task and ablated these neurons using a virally expressed caspase to determine their necessity for reward seeking., Results: Glutamatergic VP neurons exhibit little overlap with cholinergic or gamma-aminobutyric acidergic markers, the canonical VP subtypes, and exhibit distinct membrane properties. Glutamatergic VP neurons innervate and increase firing activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons. While nonselective optogenetic stimulation of the VP induced a robust place preference, selective activation of glutamatergic VP neurons induced a place avoidance. Viral ablation of glutamatergic VP neurons increased reward responding and abolished taste aversion to sucrose., Conclusions: Glutamatergic VP neurons constitute a noncanonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons and adaptively constrain reward seeking., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation targeting the subthalamic nucleus (STN-DBS) is an effective surgical treatment for the motor symptoms of Parkinson's disease (PD), the precise neuronal mechanisms of which both at molecular and network levels remain a topic of debate. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively identify changes in translational gene expression in either Drd1a-expressing striatonigral or Drd2-expressing striatopallidal medium spiny neurons (MSNs) of the striatum following STN-DBS. 6-hydroxydopamine lesioned mice received either 5 days stimulation via a DBS electrode implanted in the ipsilateral STN or 5 days sham treatment (no stimulation). Striatal polyribosomal RNA was selectively purified from either Drd2 or Drd1a MSNs using the TRAP method and gene expression profiling performed. We identified eight significantly altered genes in Drd2 MSNs (Vps33b, Ppp1r3c, Mapk4, Sorcs2, Neto1, Abca1, Penk1, and Gapdh) and two overlapping genes in Drd1a MSNs (Penk1 and Ppp1r3c) implicated in the molecular mechanisms of STN-DBS. A detailed functional analysis, using a further 728 probes implicated in STN-DBS, suggested an increased ability to receive excitation (mediated by increased dendritic spines, increased calcium influx and enhanced excitatory post synaptic potentials) accompanied by processes that would hamper the initiation of action potentials, transport of neurotransmitters from soma to axon terminals and vesicular release in Drd2-expressing MSNs. Finally, changes in expression of several genes involved in apoptosis as well as cholesterol and fatty acid metabolism were also identified. This increased understanding of the molecular mechanisms induced by STN-DBS may reveal novel targets for future non-surgical therapies for PD.

The behavioural effects of high-frequency electrical stimulation (HFS) are often similar to the effects of lesions, with the advantage of being reversible. The present study examined the effects of HFS of the nucleus accumbens (NAc), an area that has been shown to be important for sensitization to several psychostimulants, on the development and expression of EtOH sensitization. Male DBA/2 mice received five biweekly injections of EtOH (2.2 g/kg, intraperitoneally) or saline (SAL) immediately before assessments of locomotor activity (LMA). For some of the mice, each EtOH or SAL injection was preceded by 2 h of bilateral NAc HFS, whereas the remaining mice received no stimulation. Seven days after the last injection, LMA was again measured after the mice received a challenge dose of EtOH (1.8 g/kg, intraperitoneally) or SAL, either preceded or not preceded by 2 h of HFS. Mice receiving NAc HFS before EtOH injections during the sensitization period showed progressive increases in LMA that were not different from the LMA scores of EtOH-injected mice which had received no HFS. However, when the latter group was subsequently challenged after receiving HFS, a strong suppression of LMA was observed, in comparison with their own previous LMA scores (-72%) and compared with EtOH-sensitized groups challenged in the absence of HFS (-70%). A separate cohort of mice that were surgically implanted but not stimulated showed a robust EtOH sensitization response that did not differ from that of EtOH-treated mice without electrodes, demonstrating that HFS behavioural effects were not merely a result of the presence of electrodes in the NAc. These results suggest that NAc HFS may have different effects at different stages of the EtOH sensitization process, specifically suppressing expression, but not the development of EtOH sensitization. This pattern of distinct effects of NAc manipulations on different aspects of sensitization is similar to what has been reported for other drugs of abuse, suggesting a commonality of mechanisms. Our findings also suggest that the sensitization may provide a useful paradigm for the investigation of mechanisms of clinical effectiveness of HFS in humans.

Although the effects of haloperidol (HAL) have been extensively examined in experimental animals at the cellular and brain regional levels, the effects of prolonged HAL treatment on functional connectivity in the brain have not yet been addressed. Here we used expression of the immediate early gene zif268 as a marker of neural activity to examine changes in brain regional interactivity after 12 wk of HAL treatment in rats. zif268 expression was measured by in situ hybridization in 83 brain regions of HAL- and vehicle (VEH)-treated controls and correlations among all brain regions were computed separately for the two treatment groups. The strongest correlations in each group were used for network construction. It was found that VEH and HAL networks were equally segregated and integrated, and that both networks display small world organization. Compared to the VEH network, the HAL network showed enhanced interactivity between the dorsolateral striatum and thalamus, and between different subdivisions of the thalamus. It will be of interest to determine the extent to which the observed changes in functional connectivity may be related to dyskinesias, to changes in motivated behaviours and/or to the therapeutic effects of chronic HAL. By identifying the connectivity features of a chronic HAL network in the absence of other manipulations, the current findings may provide a reference signature pattern to be targeted in future efforts to discriminate between the neural bases of different behavioural outcomes arising from chronic HAL treatment.

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.

Addictive drugs such as cocaine induce synaptic plasticity in the ventral tegmental area and its projection areas, which may represent the cellular correlate of an addiction trace. Cocaine induces changes in excitatory transmission primarily in the VTA, which persists for days after a single exposure. These initial alterations in synaptic transmission represent a metaplasticity that is permissive for late stages of remodeling throughout the mesocorticolimbic circuitry, specifically in the NAc. Specific synaptic and cellular changes in the NAc persist following prolonged exposure to cocaine, and this remodeling may contribute to altered behavior. By manipulating synaptic activity in the NAc, it may be possible to reverse pathological synaptic transmission and its associated abnormal behavior following exposure to addictive drugs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) has been routinely used for the treatment of some movement disorders. However, DBS may be associated with adverse psychiatric effects, such as depression, anxiety and impulsivity., Objective: To compare DBS applied to the entopeduncular nucleus (EPN; the rodent homolog of the GPi) and STN in terms of their effects on depressive- and anxiety-like behavior in rats., Methods: DBS was applied for 21 days (4 h a day) to either the STN or EPN. Rats then underwent behavioral testing on learned helplessness and elevated plus maze tasks before being sacrificed for brain analyses of zif268, BDNF and trkB mRNA as well as BDNF protein levels., Results: Repeated DBS of the STN, but not of the EPN, led to impaired performance in the learned helplessness task, suggesting that STN-DBS induces or potentiates depressive-like behavior. There was no effect of DBS on elevated plus maze or on open field behavior. Repeated STN-DBS, but not EPN-DBS, led to decreased levels of BDNF and trkB mRNA in hippocampus. Acute stimulation of the STN or EPN resulted in similar changes in zif268 levels in several brain areas, except for the raphe where decreases were seen only after STB-DBS., Conclusions: Together these results indicate that the effects of STN- and EPN-DBS differ in behavioral and neurochemical respects. Results further suggest that the EPN may be a preferable target for clinical DBS when psychiatric side effects are considered insofar as it may be associated with a lower incidence of depressive-like behavior than the STN., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option for the motor symptoms of Parkinson's disease (PD). However, several recent studies have found an association between STN-DBS and increased impulsivity. Currently, it is not clear whether the observed increase in impulsivity results from STN-DBS per se, or whether it involves an interaction with the underlying PD neuropathology and/or intake of dopaminergic drugs. We investigated the effects of STN-DBS on performance of intact rats on two tasks measuring impulsive responding: a novel rat gambling task (rGT) and a differential reinforcement of low rate responding (DRL20s) schedule. Following initial behavioural training, animals received electrode implantation into the STN (n=24) or sham surgery (n=24), and were re-tested on their assigned behavioural task, with or without STN-DBS. Bilateral STN-DBS administered for two hours immediately prior to testing, had no effects on rGT choice behaviour or on DRL response inhibition (p>0.05). However, STN-DBS significantly increased premature responding in the rGT task (p=0.0004), an effect that took several sessions to develop and persisted in subsequent trials when no stimulation was given. Consistent with the notion of distinct facets of impulsivity with unique neurochemical underpinnings, we observed differential effects of STN-DBS in the two tasks employed. These results suggest that STN-DBS in the absence of parkinsonism may not lead to a general loss of inhibitory control, but may instead affect impulsivity under specific conditions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.

Treatment with the classic antipsychotic drugs (APDs), such as haloperidol (HAL), is associated with both acute and chronic motor side effects. Acutely, these drugs may induce extrapyramidal symptoms, whereas a prolonged treatment may result in tardive dyskinesia (TD). Atypical antipsychotics have a lower incidence of motor side effects, which have been partially ascribed to the antagonism of serotonin (5-HT) receptors. Although there is currently no satisfactory pharmacotherapy for TD, deep brain stimulation (DBS) has emerged as a promising therapy. However, the mechanisms underlying its effects remain largely unknown. DBS has been shown to affect several neurotransmitter systems, including 5-HT. In this review, we outline the involvement of 5-HT in the development of HAL-induced catalepsy and TD. We also discuss the evidence for DBS-induced alterations in 5-HT function and the relevance of serotonergic alterations to the antidyskinetic effects of DBS. The evidence suggests that the serotonergic mechanisms may be involved in the acute and chronic motor side effects of APDs as well as in adverse psychiatric effects that have been reported following DBS. However, the current evidence suggests that 5-HT alterations do not play an important role in the effectiveness of DBS in models of dyskinesias induced by chronic APDs.

Mechanisms whereby deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) reduces dyskinesias remain largely unknown. Using vacuous chewing movements (VCMs) induced by chronic haloperidol as a model of tardive dyskinesia (TD) in rats, we confirmed the antidyskinetic effects of DBS applied to the STN or entopeduncular nucleus (EPN, the rodent homolog of the GPi). We conducted a series of experiments to investigate the role of serotonin (5-HT) in these effects. We found that neurotoxic lesions of the dorsal raphe nuclei (DRN) significantly decreased HAL-induced VCMs. Acute 8-OH-DPAT administration, under conditions known to suppress raphe neuronal firing, also reduced VCMs. Immediate early gene mapping using zif268 in situ hybridization revealed that STN-DBS inhibited activity of DRN and MRN neurons. Microdialysis experiments indicated that STN-DBS decreased 5-HT release in the dorsolateral caudate-putamen, an area implicated in the etiology of HAL-induced VCMs. DBS applied to the EPN also suppressed VCMs but did not alter 5-HT release or raphe neuron activation. While these findings suggested a role for decreased 5-HT release in the mechanisms of STN DBS, further microdialysis experiments showed that when the 5-HT lowering effects of STN DBS were prevented by pretreatment with fluoxetine or fenfluramine, the ability of DBS to suppress VCMs remained unaltered. These results suggest that EPN- and STN-DBS have different effects on the 5-HT system. While decreasing 5-HT function is sufficient to suppress HAL-induced VCMs, 5-HT decrease is not necessary for the beneficial motor effects of DBS in this model.

Deep brain stimulation (DBS) has been extensively used in Parkinson's disease and is also currently being investigated in tardive dyskinesia (TD), a movement disorder induced by chronic treatment with antipsychotic drugs such as haloperidol (HAL). In rodents, vacuous chewing movements (VCMs) following chronic HAL administration are suggested to model orofacial dyskinesias in TD. We show that 60 min of DBS (100 μA, 90 μs, 130 Hz) applied to the entopeduncular (EPN) or subthalamic (STN) nuclei significantly decreases HAL-induced VCMs. Using zif268 as a neural activity marker, we found that in HAL-treated animals EPN stimulation increased zif268 mRNA levels in the globus pallidus (+65%) and substantia nigra compacta (+62%) and reticulata (+76%), while decreasing levels in the motor cortex and throughout the thalamus. In contrast, after STN DBS zif268 levels in HAL-treated animals decreased in all basal ganglia structures, thalamus and motor cortex (range: 29% in the ventrolateral caudate-putamen to 100% in the EPN). Local tissue inactivation by muscimol injections into the STN or EPN also reduced VCMs, but to a lesser degree than DBS. When applied to the EPN muscimol decreased zif268 levels in substantia nigra (-29%), whereas STN infusions did not result in significant zif268 changes in any brain area. These results confirm the effectiveness of DBS in reducing VCMs and suggest that tissue inactivation does not fully account for DBS effects in this preparation. The divergent effects of STN vs. EPN manipulations on HAL-induced zif268 changes suggest that similar behavioral outcomes of DBS in these two areas may involve different neuroanatomical mechanisms., (Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.)

Alzheimer's disease (AD) is the most prevalent form of dementia, affecting an estimated 4.8 million people in North America. For the past decade, the amyloid cascade hypothesis has dominated the field of AD research. This theory posits that the deposition of amyloid-beta protein (Abeta) in the brain is the key pathologic event in AD, which induces a series of neuropathological changes that manifest as cognitive decline and eventual dementia. Based on this theory, interventions that reduce Abeta burden in the brain would be expected to alleviate both the neuropathological changes and dementia, which characterize AD. Several diverse pharmacological strategies have been developed to accomplish this. These include inhibiting the formation of Abeta, preventing the aggregation of Abeta into insoluble aggregates, preventing the entry of Abeta into the brain from the periphery and enhancing the clearance of Abeta from the central nervous system. To date, no amyloid-modifying therapy has yet been successful in phase 3 clinical trials; however, several trials are currently underway. This article provides a review of the status of amyloid-modifying therapies and the implications for the amyloid cascade hypothesis.