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The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating negatively motivated behaviour and its implication in major depression. The LHb, sometimes referred to as the brain’s ‘antireward centre’, receives inputs from diverse limbic forebrain and basal ganglia structures, and targets essentially all midbrain neuromodulatory systems, including the noradrenergic, serotonergic and dopaminergic systems. Its unique anatomical position enables the LHb to act as a hub that integrates value-based, sensory and experience-dependent information to regulate various motivational, cognitive and motor processes. Dysfunction of the LHb may contribute to the pathophysiology of several psychiatric disorders, especially major depression. Recently, exciting progress has been made in identifying the molecular and cellular mechanisms in the LHb that underlie negative emotional state in animal models of drug withdrawal and major depression. A future challenge is to translate these advances into effective clinical treatments.The lateral habenula (LHb) has received increasing attention in part because dysfunction of this region may play a part in several psychiatric disorders, notably depression. In this Review, Hu et al. examine the neural circuits, physiological functions and potential pathophysiological roles of the LHb.

The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson’s disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD. Here, the authors use cell-type specific stimulation of brainstem neurons within the caudal pedunculopontine nucleus to show that activation of excitatory neurons can normalize severe locomotor deficit in mouse models of parkinsonism. The study defines a potential target for neuromodulatory restoration of locomotor function in Parkinson’s disease.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior. The authors identify a spinal–parabrachial–mesencephalic circuit that regulates the activity of dopamine neurons during pain.

IntroductionChronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in patients with cough is an enhanced sensitivity of the respiratory system to stimuli that subsequently evoke excessive coughing. The aetiology of this ‘cough hypersensitivity syndrome’ is unclear but believed to involve hypersensitivity of the sensory neural pathways that innervate the airways and lungs.MethodsIn the present study, we used functional brain imaging to compare central neural responses to airway stimulation using inhaled capsaicin in healthy people and patients with cough hypersensitivity.ResultsHypersensitivity in response to inhaled capsaicin coincided with elevated neural activity in the midbrain in a region encompassing the nucleus cuneiformis (left: p<0.001; right: p<0.001) and periaqueductal gray (p=0.008) in comparison to normal sensitivity in controls. The enhanced activity noted in the midbrain is similar to that occurring in patients with chronic pain, thus providing empirical evidence to support the notion that cough and pain share neurobiological similarities. Furthermore, patients with cough hypersensitivity displayed difficulty controlling their cough, which manifested as a failure to suppress cough during capsaicin challenge (ie, reduced cough frequency) in controls compared with patients with cough hypersensitivity (p=0.046). Cough suppression was associated with reduced activity in a forebrain network that included the dorsomedial prefrontal and anterior mid-cingulate cortices. Additionally, cough frequency was correlated with activity in the right inferior frontal gyrus (R2=0.6, p<0.001) and right anterior insula (R2=0.6, p<0.001), regions previously implicated in voluntary cough suppression.ConclusionsThese findings provide insight into the central neurobiology of cough hypersensitivity and suggest that both central amplification of cough sensory inputs and reduced capacity to suppress cough motor behaviours define patients with problematic cough.

Age-related deficits in speech-in-noise understanding pose a significant problem for older adults. Despite the vast number of studies conducted to investigate the neural mechanisms responsible for these communication difficulties, the role of central auditory deficits, beyond peripheral hearing loss, remains unclear. The current study builds upon our previous work that investigated the effect of aging on normal-hearing individuals and aims to estimate the effect of peripheral hearing loss on the representation of speech in noise in two critical regions of the aging auditory pathway: the midbrain and cortex. Data from 14 hearing-impaired older adults were added to a previously published dataset of 17 normal-hearing younger adults and 15 normal-hearing older adults. The midbrain response, measured by the frequency-following response (FFR), and the cortical response, measured with the magnetoencephalography (MEG) response, were recorded from subjects listening to speech in quiet and noise conditions at four signal-to-noise ratios (SNRs): +3, 0, -3, and -6 dB sound pressure level (SPL). Both groups of older listeners showed weaker midbrain response amplitudes and overrepresentation of cortical responses compared to younger listeners. No significant differences were found between the two older groups when the midbrain and cortical measurements were analyzed independently. However, significant differences between the older groups were found when investigating the midbrain-cortex relationships; that is, only hearing-impaired older adults showed significant correlations between midbrain and cortical measurements, suggesting that hearing loss may alter reciprocal connections between lower and higher levels of the auditory pathway. The overall paucity of differences in midbrain or cortical responses between the two older groups suggests that age-related temporal processing deficits may contribute to older adults' communication difficulties beyond what might be predicted from peripheral hearing loss alone; however, hearing loss does seem to alter the connectivity between midbrain and cortex. These results may have important ramifications for the field of audiology, as it indicates that algorithms in clinical devices, such as hearing aids, should consider age-related temporal processing deficits to maximize user benefit.

A spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions. Deep brain stimulation and epidural electrical stimulation of the spinal cord enable locomotion in humans with spinal cord injury (SCI) but the potential synergy between both approaches is unclear. The authors show that a complex technological approach is required to enable volitional walking in rats with SCI.

Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is rapidly increasing and needs to be efficiently organized, so that the resulting data is available for exploration and analysis. Here we introduce a computationally tractable, comprehensive molecular interaction map of PD. This map integrates pathways implicated in PD pathogenesis such as synaptic and mitochondrial dysfunction, impaired protein degradation, alpha-synuclein pathobiology and neuroinflammation. We also present bioinformatics tools for the analysis, enrichment and annotation of the map, allowing the research community to open new avenues in PD research. The PD map is accessible at http://minerva.uni.lu/pd_map .

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors. Mice exposed to a two-bottle alcohol choice paradigm can be divided into high and low drinking groups. Here, the authors show that stimulating VTA neurons to induce higher phasic activity patterns that are observed in low alcohol drinking mice, suppresses alcohol drinking in mice that are high alcohol drinking.

Over the past 15 years the use of transcranial B-mode sonography to assess brainstem and subcortical brain structures has become an important tool for the diagnosis and differential diagnosis of various movement disorders. The most widely recognised finding for movement disorders has been an increase in echogenicity of the substantia nigra, an area of the midbrain that is affected in idiopathic Parkinson's disease (PD). This finding has enabled the reliable diagnosis of PD with high predictive values. Other sonographic features, such as hypoechogenicity of the brainstem midline and hyperechogenicity of the lentiform nucleus, might help the differential diagnosis of PD and other movement disorders. This Review provides detailed information about the advantages and limitations of this novel neuroimaging method, including guidelines for the scanning procedure and considerations on the origin of ultrasound abnormalities. We discuss the use of transcranial sonography for early and preclinical diagnosis and for differential diagnosis of PD and other movement disorders, and we compare this method with other functional neuroimaging strategies. Transcranial B-mode sonography is a reliable, non-invasive, commonly available, easily applicable, and inexpensive method, which provides new information about the morphology of the brain to help the diagnosis of various movement disorders. Thus, this neuroimaging method could be recommended for general application in the diagnosis and differential diagnosis of PD.

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [ 11 C]raclopride and [ 11 C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P <0.001) and was significantly correlated with D2/D3 receptors (accumbens: r =0.39, P <0.008; midbrain: r =0.41, P <0.005) and transporters (accumbens: r =0.35, P <0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor—and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.