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Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for the motor symptoms of movement disorders including Parkinson's 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-DBS per se from concurrent reduction of dopamine replacement therapy, from underlying PD pathology or from disease progression. To this end, pre-clinical models allow for the dissociation of each of these factors, and to establish neural substrates underlying the emergence of motivational symptoms following STN-DBS. Here, we performed a systematic analysis of rodent studies assessing the effects of STN-DBS on reward seeking, reward motivation and reward consumption across a variety of behavioral paradigms. We find that STN-DBS decreases reward seeking in the majority of experiments, and we outline how design of the behavioral task and DBS parameters can influence experimental outcomes. While an early hypothesis posited that DBS acts as a “functional lesion,” an analysis of lesions and inhibition of the STN revealed no consistent pattern on reward-related behavior. Thus, we discuss alternative mechanisms that could contribute to the amotivational effects of STN-DBS. We also argue that optogenetic-assisted circuit dissection could yield important insight into the effects of the STN on motivated behavior in health and disease. Understanding the mechanisms underlying the effects of STN-DBS on motivated behavior-will be critical for optimizing the clinical application of STN-DBS.

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. 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.

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.

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. Obesity and anorexia nervosa are two health conditions related to food intake. Researchers studying these disorders in animal models need to both measure food intake and assess behavioural factors: that is, why animals seek and consume food. Measuring an animal’s food intake is usually done by weighing food containers. However, this can be inaccurate due to the small amount of food that rodents eat. As for studying feeding motivation, this can involve calculating the number of times an animal presses a lever to receive a food pellet. These tests are typically conducted in hour-long sessions in temporary testing cages, called operant boxes. Yet, these tests only measure a brief period of a rodent's life. In addition, it takes rodents time to adjust to these foreign environments, which can introduce stress and may alter their feeding behaviour. To address this, Matikainen-Ankney, Earnest, Ali et al. developed a device for monitoring food intake and feeding behaviours around the clock in rodent home cages with minimal experimenter intervention. This ‘Feeding Experimentation Device’ (FED3) features a pellet dispenser and two ‘nose-poke’ sensors to measure total food intake, as well as motivation for and learning about food rewards. The battery-powered, wire-free device fits in standard home cages, enabling long-term studies of feeding behaviour with minimal intervention from investigators and less stress on the animals. This means researchers can relate data to circadian rhythms and meal patterns, as Matikainen-Ankney did here. Moreover, the device software is open-source so researchers can customise it to suit their experimental needs. It can also be programmed to synchronise with other instruments used in animal experiments, or across labs running the same behavioural tasks for multi-site studies. Used in this way, it could help improve reproducibility and reliability of results from such studies. In summary, Matikainen-Ankney et al. have presented a new practical solution for studying food-related behaviours in mice and rats. Not only could the device be useful to researchers, it may also be suitable to use in educational settings such as teaching labs and classrooms.

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. Fang and Creed review and synthesize recent studies of the striatum and pallidal complex. Based on connectivity and organization of striatal–pallidal pathways in rodents, they propose how these structures coordinate learning and flexible behavior.

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. Dopamine-independent induction of long-term potentiation at hippocampal synapses onto the nucleus accumbens modulates reward-related behaviour.

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.

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. Markovic et al. demonstrate in rodents that anhedonia-like states in inflammatory pain are mediated through increased inhibitory control and subsequent diminished activity of mesolimbic dopamine neurons.

Cocaine-induced synaptic plasticity can be reversed in mice with optogenetically inspired deep brain stimulation A major challenge in treating many neuropsychiatric disorders is that diagnoses are regularly based on behavior rather than on biomarkers, as well as the fact that such conditions are often not associated with gross structural brain changes. Addiction is one example of a disorder defined by pathological behavior (drug seeking despite harmful consequences) in which there is no significant loss of neurons and for which there is no cure.