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The cerebellum is involved in many motor, autonomic and cognitive functions, and new tasks that have a cerebellar contribution are discovered on a regular basis. Simultaneously, our insight into the functional compartmentalization of the cerebellum has markedly improved. Additionally, studies on cerebellar output pathways have seen a renaissance due to the development of viral tracing techniques. To create an overview of the current state of our understanding of cerebellar efferents, we undertook a systematic review of all studies on monosynaptic projections from the cerebellum to the brainstem and the diencephalon in mammals. This revealed that important projections from the cerebellum, to the motor nuclei, cerebral cortex, and basal ganglia, are predominantly di- or polysynaptic, rather than monosynaptic. Strikingly, most target areas receive cerebellar input from all three cerebellar nuclei, showing a convergence of cerebellar information at the output level. Overall, there appeared to be a large level of agreement between studies on different species as well as on the use of different types of neural tracers, making the emerging picture of the cerebellar output areas a solid one. Finally, we discuss how this cerebellar output network is affected by a range of diseases and syndromes, with also non-cerebellar diseases having impact on cerebellar output areas.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.

This Resource chronicles dynamic gene expression patterns in the developing hypothalamus from embryonic day 10.5 through maturity. The authors find that Shh must be expressed in the hypothalamic basal plate for differentiation of the anterior and tuberal hypothalamic nuclei. The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.

Key Points Mesodiencepahlic dopaminergic (mdDA) neurons consist of multiple molecular and functional distinguishable subsets, besides the 'old' anatomical definition of the substantia nigra pars compacta and the ventral tegmental area. Subset specification is established through specific molecular coding of the ventricular zone in dorsoventral and rostrocaudal axes. A combination of several signalling molecules including retinoic acid, WNTs, sonic hedgehog and transforming growth factors, as well as neurotrophic factors including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, influence the emergence and survival of mdDA neurons in addition to cell intrinsic molecular coding. Specific mdDA subsets define specific connectivity to the forebrain regions such as the striatum and prefrontal cortex, providing specific functional networks. Guidance molecules from the netrin–DCC (deleted in colorectal cancer), ROBO–SLIT and semaphorin–plexin–neuropilin pathways are essential for providing initial guidance rules to direct outgrowing mdDA axons towards the ventral forebrain. Molecular programmes for mdDA development form the basis for embryonic stem (ES) cell engineering of mdDA neurons, including subset specification. Transplantation paradigms with engineered ES cells, stem cells that are induced to develop the mdDA phenotype or embryonic mdDA cells should include axon guidance rules to ensure proper interactions and connectivity with striatal targets. Understanding the mechanisms involved in the development of mesodiencephalic dopaminergic neurons might contribute to the success of cell-replacement strategies for disorders such as Parkinson's disease. Smidt and Burbach review the factors governing specification, migration, differentiation and maintenance of these neurons. Dopaminergic neurons located in the ventral mesodiencephalon are essential for the control of voluntary movement and the regulation of emotion, and are severely affected in neurodegenerative diseases such as Parkinson's disease. Recent advances in molecular biology and mouse genetics have helped to unravel the mechanisms involved in the development of mesodiencephalic dopaminergic (mdDA) neurons, including their specification, migration and differentiation, as well as the processes that govern axonal pathfinding and their specific patterns of connectivity and maintenance. Here, we follow the developmental path of these neurons with the goal of generating a molecular code that could be exploited in cell-replacement strategies to treat diseases such as Parkinson's disease.

The thalamus is a small, bilateral structure in the diencephalon that integrates signals from many areas of the CNS. This critical anatomical position allows the thalamus to influence whole-brain activity and adaptive behaviour. However, traditional research paradigms have struggled to attribute specific functions to the thalamus, and it has remained understudied in the human neuroimaging literature. Recent advances in analytical techniques and increased accessibility to large, high-quality data sets have brought forth a series of studies and findings that (re-)establish the thalamus as a core region of interest in human cognitive neuroscience, a field that otherwise remains cortico-centric. In this Perspective, we argue that using whole-brain neuroimaging approaches to investigate the thalamus and its interaction with the rest of the brain is key for understanding systems-level control of information processing. To this end, we highlight the role of the thalamus in shaping a range of functional signatures, including evoked activity, interregional connectivity, network topology and neuronal variability, both at rest and during the performance of cognitive tasks.The thalamus is a subcortical structure that is highly interconnected with various brain regions. In this Perspective, Kai Hwang and colleagues examine the role of the human thalamus in the systems-level control of information processing.

Sleep and wakefulness control in the mammalian brain requires the coordination of various discrete interconnected neurons. According to the most conventional sleep model, wake-promoting neurons (WPNs) and sleep-promoting neurons (SPNs) compete for network dominance, creating a systematic “switch” that results in either the sleep or awake state. WPNs and SPNs are ubiquitous in the brainstem and diencephalon, areas that together contain <1% of the neurons in the human brain. Interestingly, many of these WPNs and SPNs co-express and co-release various types of the neurotransmitters that often have opposing modulatory effects on the network. Co-transmission is often beneficial to structures with limited numbers of neurons because it provides increasing computational capability and flexibility. Moreover, co-transmission allows subcortical structures to bi-directionally control postsynaptic neurons, thus helping to orchestrate several complex physiological functions such as sleep. Here, we present an in-depth review of co-transmission in hypothalamic WPNs and SPNs and discuss its functional significance in the sleep–wake network.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairment in the formation of longterm, declarative memory (anterograde amnesia), together with temporally graded retrograde amnesia covering ∼5 y prior to the cardiac arrest. More remote memory for both facts and autobiographical events was intact. His neuropathology was extensive and involved the medial temporal lobe, the diencephalon, cerebral cortex, basal ganglia, and cerebellum. In the hippocampal formation, there was substantial cell loss in the CA1 and CA3 fields, the hilus of the dentate gyrus (with sparing of granule cells), and the entorhinal cortex. There was also cell loss in the CA2 field, but some remnants remained. The amygdala demonstrated substantial neuronal loss, particularly in its deep nuclei. In the thalamus, there was damage and atrophy of the anterior nuclear complex, the mediodorsal nucleus, and the pulvinar. There was also loss of cells in the medial and lateral mammillary nuclei in the hypothalamus. We suggest that the neuropathology resulted from two separate factors: the initial cardiac arrest (and respiratory distress) and the recurrent seizures that followed, which led to additional damage characteristic of temporal lobe epilepsy.

The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development. Eze et al. use single-cell sequencing and immunohistochemical validation to create an atlas of early human brain development. In the telencephalon, they discover a diversity of progenitor subtypes, including two that are enriched in humans.

Fipronil (FIP) is a highly effective insecticide that has been used in agriculture and veterinary medicine. Its neurotoxic effect to insects and to non-target organisms, after nonintentional exposure, was reported. Many studies were conducted to evaluate FIP effects on mammals. However, slight is known about its effect on the brain stem and diencephalon. The current study was designed to investigate the ability of FIP to induce oxidative stress as a molecular mechanism of FIP neurotoxicity that resulted in apoptosis and neural tissue reactivity in these regions. Ten adult male rats received 10 mg/kg of FIP technical grade by oral gavage, daily for 45 days. Brain stem and diencephalon were processed to examine oxidative stress–induced macromolecular alteration (MDA, PCC and DNA fragmentation). Also, the histopathological assessment and immunoreactivity for caspase-3 (active form), iNOS and GFAP were performed on the thalamus, hypothalamus and medulla oblongata. Our results revealed that FIP significantly raised MDA, PCC and DNA fragmentation ( p ≤ 0.05). In addition, significantly increased immunoreactivity to GFAP, iNOS and caspase-3 (active form) in the FIP-treated group was noticed ( p ≤ 0.05). Moreover, alterations in the histoarchitecture of the neural tissue of these regions were observed. We conclude that FIP can induce oxidative stress, leading to apoptosis and tissue reaction in brain stem and diencephalon.