Single-cell transcriptomic approaches are revolutionizing neuroscience. Integrating this wealth of data with morphology and physiology, for the comprehensive study of neuronal biology, requires multiplexing gene expression data with complementary techniques. To meet this need, multiple groups in parallel have developed “Patch-seq,” a modification of whole-cell patch-clamp protocols that enables mRNA sequencing of cell contents after electrophysiological recordings from individual neurons and morphologic reconstruction of the same cells. In this review, we first outline the critical technical developments that enabled robust Patch-seq experimental efforts and analytical solutions to interpret the rich multimodal data generated. We then review recent applications of Patch-seq that address novel and long-standing questions in neuroscience. These include the following: (1) targeted study of specific neuronal populations based on their anatomic location, functional properties, lineage, or a combination of these...

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.

Substance use disorder (SUD) is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose–response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and Npas2 mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all Npas2 mutants. Sex differences emerged during the dark (active) phase with Npas2 mutation increasing self-administration, extinction responding, and reinstatement only in females as well as reinforcement and motivation in males and females. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and Npas2 mutant females and confirmed that u...

fMRI research has revealed that cerebellar lobule VIIb/VIIIa exhibits load-dependent activity that increases with the number of items held in visual working memory (VWM). However, it remains unclear whether these cerebellar responses reflect processes specific to VWM or more general visual attentional mechanisms. To investigate this question, we examined whether cerebellar activity during the delay period of a VWM task is selective for stimuli held in working memory. A sample of male and female human subjects performed a VWM continuous report task in which they were retroactively cued to remember the direction of motion of moving dot stimuli. Cerebellar lobule VIIb/VIIIa delay-period activation accurately decoded the direction of the remembered stimulus, as did frontal and parietal regions of the dorsal attention network. Arguing against a motor explanation, no other cerebellar area exhibited stimulus specificity, including the oculomotor vermis, a key area associated with eye movement control. Finer-scale...

Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.

A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use disorder. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epigenome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.

The ability to perceive and produce movements in the real world with precise timing is critical for survival in animals, including humans. However, research on sensorimotor timing has rarely considered the tight interrelation between perception, action, and cognition. In this review, we present new evidence from behavioral, computational, and neural studies in humans and nonhuman primates, suggesting a pivotal link between sensorimotor control and temporal processing, as well as describing new theoretical frameworks regarding timing in perception and action. We first discuss the link between movement coordination and interval-based timing by addressing how motor training develops accurate spatiotemporal patterns in behavior and influences the perception of temporal intervals. We then discuss how motor expertise results from establishing task-relevant neural manifolds in sensorimotor cortical areas and how the geometry and dynamics of these manifolds help reduce timing variability. We also highlight how neu...

The sensory and cognitive abilities of the mammalian neocortex are underpinned by intricate columnar and laminar circuits formed from an array of diverse neuronal populations. One approach to determining how interactions between these circuit components give rise to complex behavior is to investigate the rules by which cortical circuits are formed and acquire functionality during development. This review summarizes recent research on the development of the neocortex, from genetic determination in neural stem cells through to the dynamic role that specific neuronal populations play in the earliest circuits of neocortex, and how they contribute to emergent function and cognition. While many of these endeavors take advantage of model systems, consideration will also be given to advances in our understanding of activity in nascent human circuits. Such cross-species perspective is imperative when investigating the mechanisms underlying the dysfunction of early neocortical circuits in neurodevelopmental disorder...

Each year, JNeurosci publishes a group of review articles based on topics presented in symposia and mini-symposia at the annual meeting of the Society for Neuroscience. These reviews are usually published in a special issue the week before the meeting. Sadly, the 2020 annual meeting was canceled

Speech processing relies on interactions between auditory and motor systems and is asymmetrically organized in the human brain. The left auditory system is specialized for processing of phonemes, whereas the right is specialized for processing of pitch changes in speech affecting prosody. In speakers of tonal languages, however, processing of pitch (i.e., tone) changes that alter word meaning is left-lateralized indicating that linguistic function and language experience shape speech processing asymmetries. Here, we investigated the asymmetry of motor contributions to auditory speech processing in male and female speakers of tonal and non-tonal languages. We temporarily disrupted the right or left speech motor cortex using transcranial magnetic stimulation (TMS) and measured the impact of these disruptions on auditory discrimination (mismatch negativity; MMN) responses to phoneme and tone changes in sequences of syllables using electroencephalography (EEG). We found that the effect of motor disruptions on ...