Axon pathfinding is essential for the establishment of proper neuronal connections during development. Advances in neuroimaging and genomic technologies, coupled with animal modeling, are leading to the identification of an increasing number of human disorders that result from aberrant axonal wiring. In this review, we summarize the recent clinical, genetic and molecular advances with regard to three human disorders of axon guidance: Horizontal gaze palsy with progressive scoliosis, Congenital mirror movements, and Congenital fibrosis of the extraocular muscles, Type III.
Fragile X syndrome (FXS) is a common form of mental disability and one of the known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeats which leads to DNA methylation of the fragile X mental retardation gene 1 (FMR1) and transcriptional silencing, resulting in the absence of fragile X mental retardation protein (FMRP), an mRNA binding protein. Although it is widely known that FMRP is critical for metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), which has provided a general theme for developing pharmacological drugs for FXS, specific downstream targets of FMRP may also be of therapeutic value. Since alterations in potassium channel expression level or activity could underlie neuronal network defects in FXS, here we describe recent findings on how these channels might be altered in mouse models of FXS and the possible therapeutic avenues for treating FXS.
fragile X syndrome; FMRP; mGluR theory; potassium channels
Recent discoveries concerning the architecture and cellular dynamics of the developing human brain are revealing new differences between mouse and human cortical development. In mice, neurons are produced by ventricular radial glial (RG) cells, or subventricular zone intermediate progenitor (IP) cells. In the human cortex, both ventricular RG and highly motile outer RG cells generate IP cells, which likely undergo multiple rounds of transit amplification in the outer subventricular zone before producing neurons. This creates a more complex environment for neurogenesis and neuronal migration, adding new arenas in which neurodevelopmental disease gene mutation could disrupt corticogenesis. A more complete understanding of disease mechanisms will involve use of emerging model systems with developmental programs more similar to that of the human neocortex.
Many candidate genes are now thought to confer susceptibility to autism spectrum disorder (ASD). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this context, progress in deciphering the molecular architecture of cellular protein-protein interactions together with the unraveling of synaptic dysfunction in neural networks may prove pivotal to advancing our understanding of ASDs.
As astrocytes are becoming recognized as important mediators of normal brain function, studies into their roles in neurological disease have gained significance. Across mouse models for neurodevelopmental and neurodegenerative diseases, astrocytes are considered key regulators of disease progression. In Rett syndrome and Parkinson’s disease, astrocytes can even initiate certain disease phenotypes. Numerous potential mechanisms have been offered to explain these results, but research into the functions of astrocytes in disease is just beginning. Crucially, in vivo verification of in vitro data is still necessary, as well as a deeper understanding of the complex and relatively unexplored interactions between astrocytes, oligodendrocytes, microglia, and neurons.
Continuously generated new neurons promote circuitry plasticity within specialized regions and contribute to specific functions of adult mammalian brain. A number of recent studies have investigated the cellular origin of adult neurogenesis in the hippocampus, yielding divergent models of neural stem cell behavior. An essential question remains whether these models are overlapping or fundamentally discrete. We review evidence that primary neural precursors in the adult hippocampus exhibit significant heterogeneity in their properties of self-renewal, multi-lineage differentiation and regulation, representing a range from unipotential committed precursors to bona fide self-renewing multipotent neural stem cells. We further present a testable unifying hypothesis of adult neural stem cell behavior in vivo to outline a common framework for future studies of molecular and cellular mechanisms regulating adult neural stem cells and how these cells may contribute to hippocampal function and repair.
Brain tumors are devastating due to the high fatality rate and the devastating impact on life qualities of patients. Recent advancement of comparative transcriptome profiling tools and mouse genetic models has greatly deepened our understanding of the developmental origins of these tumors, which could lead to effective therapeutic strategies. We review recent progresses in three types of brain tumors: ependymoma, medulloblastoma, and malignant glioma. The conceptual framework established by these studies converged on three important aspects. First, subtypes in each tumor group originate from distinct cell types. Second, each cell-of-origin is uniquely sensitive to some but not other genetic mutations. Lastly, mutant stem cells may not transform until they differentiate into more restricted progenitor cell type. Overall, these findings indicate the existence of intricate interactions between gene mutations and developmental context for the formation of brain tumors.
Down syndrome (DS) is a multi-faceted condition resulting in the most common genetic form of intellectual disability. Mouse models of DS, especially the Ts65Dn model, have been pivotal in furthering our understanding of the genetic, molecular and neurobiological mechanisms that underlie learning and memory impairments in DS. Cognitive and pharmacological insights from the Ts65Dn mouse model have led to remarkable translational progress in the development of therapeutic targets and in the emergence of DS clinical trials. Unravelling the pathogenic role of trisomic genes on human chromosome 21 and the genotype-phenotype relationship still remains a pertinent goal for tackling cognitive deficits in DS.
X-linked Infantile Spasms Syndrome (ISSX) is a catastrophic epilepsy of early childhood with intractable seizures, intellectual disability, and poor prognosis. A spectrum of mutations in the Aristaless-Related Homeobox gene (ARX) has been linked to ISSX, and downstream targets of this interneuron-expressed transcription factor are being defined. Recent advances combining in vitro and in vivo methods have unveiled complex interactions between Arx and its binding partners and their effects on cell migration and maturation that can help explain the diversity of ARX phenotypes. New mutant mouse models of Arx-induced pathology, including a recent human triplet-repeat expansion mutation with a phenotype of infantile spasms and electrographic seizures, provide valuable tools for exploring the pathophysiology of Arx and substrates for testing novel therapies.
A major task of the central nervous system (CNS) is to control behavioral actions, which necessitates a precise regulation of muscle activity. The final components of the circuitry controlling muscles are the motorneurons, which settle into pools in the ventral horn of the spinal cord in positions that mirror the musculature organization within the body. This ‘musculotopic’ motor-map then becomes the internal CNS reference for the neuronal circuits that control motor commands. This review describes recent progress in defining the neuroanatomical organization of the higher-order motor circuits in the cortex and spinal cord, and our current understanding of the integrative features that contribute to complex motor behaviors. We highlight emerging evidence that cortical and spinal motor command centers are loosely organized with respect to the musculotopic spatial-map, but these centers also incorporate organizational features that associate with the function of different muscle groups during commonly enacted behaviors.
The cellular and molecular mechanisms of neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The unavailability of live patient neurons for research, however, has represented a major obstacle in the elucidation of the disease etiologies. Recently, the development of induced pluripotent stem cell (iPSC) technology allows for the generation of human neurons from somatic cells of patients. We review ongoing studies using iPSCs as an approach to model neurodevelopmental disorders, the promise and caveats of this technique and its potential for drug screening. The reproducible findings of relevant phenotypes in Rett syndrome iPSC-derived neurons suggest that iPSC technology offers a novel and unique opportunity for the understanding of and the development of therapeutics for other autism spectrum disorders.
Genetic disorders that present with a high incidence of autism spectrum disorders (ASD) offer tremendous potential both for elucidating the underlying neurobiology of ASD and identifying therapeutic drugs and/or drug targets. As a result, clinical trials for genetic disorders associated with ASD are no longer a hope for the future but rather an exciting reality whose time has come. Tuberous sclerosis complex (TSC) is one such genetic disorder that presents with ASD, epilepsy, and intellectual disability. Cell culture and mouse model experiments have identified the mTOR pathway as a therapeutic target in this disease. This review summarizes the advantages of using TSC as model of ASD and the recent advances in the translational and clinical treatment trials in TSC.
•Neurodegenerative diseases are characterised by disordered sleep/wake patterns.•Aggregation of soluble proteins is the canonical molecular motif of neurodegeneration.•Local circadian clocks direct processes influencing pro-neurodegenerative aggregation.•Thus, circadian/sleep–wake timing and neurodegeneration are reciprocally dependent.•Revealing the feedback between clocks and neurodegeneration may suggest new therapies.
The major neurodegenerative diseases are characterised by a disabling loss of the daily pattern of sleep and wakefulness, which may be reflective of a compromise to the underlying circadian clock that times the sleep cycle. At a molecular level, the canonical property of neurodegenerative diseases is aberrant aggregation of otherwise soluble neuronal proteins. They can thus be viewed as disturbances of proteostasis, raising the question whether the two features — altered daily rhythms and molecular aggregation — are related. Recent discoveries have highlighted the fundamental contribution of circadian clocks to the correct ordering of daily cellular metabolic cycles, imposing on peripheral organs such as the liver a strict programme that alternates between anabolic and catabolic states. The discovery that circadian mechanisms are active in local brain regions suggests that they may impinge upon physiological and pathological elements that influence pro-neurodegenerative aggregation. This review explores how introducing the dimension of circadian time and the circadian clock might refine the analysis of aberrant aggregation, thus expanding our perspective on the cell biology common to neurodegenerative diseases.
Exposure to addictive drugs can result in maladaptive alterations in neural circuit function. This review highlights recent progress made in identifying the organization, function, and cellular plasticity of the ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions strongly implicated in substance use disorders. Emphasis is given to advances made with new research methodologies, particularly optogenetics, which have provided scientists with an unprecedented ability to map neural circuitry and pinpoint drug-induced synaptic modifications. A better understanding of these adaptive events will aid the development of pharmacological treatments for drug addiction and, more generally, further our understanding of motivated behaviors.
Learning and memory and navigation literatures emphasize interactions between multiple memory systems: a flexible, planning-based system and a rigid, cached-value system. This has profound implications for decision-making. Recent conceptualizations of flexi-ble decision-making employ prospection and projection arising from a network involving the hippocampus. Recent recordings from rodent hippocampus in decision-making situations have found transient forward-shifted representations. Evaluation of that prediction and subsequent action-selection likely occurs downstream (e.g. in orbitofrontal cortex, in ventral and dorsomedial striatum). Classically, striatum has been identified as a critical component of the less-flexible, incremental system. Current evidence, however, suggests that striatum is involved in both flexible and stimulus-response decision-making, with dorsolateral striatum involved in stimulus-response strategies and ventral and dorsomedial striatum involved in goal-directed strategies.
Synapses made by local interneurons dominate the intrinsic circuitry of the mammalian visual thalamus and influence all signals traveling from the eye to cortex. Here we draw on physiological and computational analyses of receptive fields in the cat's lateral geniculate nucleus to describe how inhibition helps to enhance selectivity for stimulus features in space and time and to improve the efficiency of the neural code. Further, we explore specialized synaptic attributes of relay cells and interneurons and discuss how these might be adapted to preserve the temporal precision of retinal spike trains and thereby maximize the rate of information transmitted downstream.
The controlled cutting of tissue with laser light is a natural technology to combine with automated stereotaxic surgery. A central challenge is to control the cutting of hard tissue, such as bone, without inducing damage to juxtaposed soft tissue, such as nerve and dura. We review past work that demonstrates the feasibility of such control through the use of ultrafast laser light to both cut and generate optical feedback signals via second harmonic generation and laser induced plasma spectra.
Drosophila melanogaster has historically been the premier model system for understanding the molecular and genetic bases of complex behaviors. In the last decade technical advances, in the form of new genetic tools and electrophysiological and optical methods, have allowed investigators to begin to dissect the neuronal circuits that generate behavior in the adult. The blossoming of circuit analysis in this organism has also reinforced our appreciation of the inadequacy of wiring diagrams for specifying complex behavior. Neuromodulation and neuronal plasticity act to reconfigure circuits on both short and long time scales. These processes act on the connectome, providing context by integrating external and internal cues that are relevant for behavioral choices. New approaches in the fly are providing insight into these basic principles of circuit function.
Neuropeptides provide functional flexibility to microcircuits, their inputs and effectors by modulating pre- and postsynaptic properties and intrinsic currents. Recent studies have relied less on applied neuropeptide and more on their neural release. In rhythmically active microcircuits (central pattern generators, CPGs), recent studies show that neuropeptide modulation can activate particular activity patterns by organizing specific circuit motifs. Neuropeptides can also modify microcircuit output indirectly, by modulating circuit inputs. Recently elucidated consequences of neuropeptide modulation include changes in motor patterns and behavior, stabilization of rhythmic motor patterns and changes in CPG sensitivity to sensory input. One aspect of neuropeptide modulation that remains enigmatic is the presence of multiple peptide family members in the same nervous system and even the same neurons.
Spinal cord development is a complex process involving generation of the appropriate number of cells, acquisition of distinctive phenotypes and establishment of functional connections that enable execution of critical functions such as sensation and locomotion. Here we review the basic cellular events occurring during spinal cord development, highlighting studies that demonstrate the roles of electrical activity in this process. We conclude that the participation of different forms of electrical activity is evident from the beginning of spinal cord development and intermingles with other developmental cues and programs to implement dynamic and integrated control of spinal cord function.
This review summarizes the latest developments in our understanding of amygdala networks that support classical fear conditioning, the experimental paradigm most commonly used to study learned fear in the laboratory. These recent advances have considerable translational significance as congruent findings from studies of fear learning in animals and humans indicate that anxiety disorders result from abnormalities in the mechanisms that normally regulate conditioned fear. Due to the introduction of new techniques and the continued use of traditional approaches, it is becoming clear that conditioned fear involves much more complex networks than initially believed, including coordinated interactions between multiple excitatory and inhibitory circuits within the amygdala.
amygdala; fear conditioning; emotions; learning; memory
The postural system maintains a specific body orientation and equilibrium during standing and during locomotion in the presence of many destabilizing factors (external and internal). Numerous studies in humans have revealed essential features of the functional organization of this system. Recent studies on different animal models have significantly supplemented human studies. They have greatly expanded our knowledge of how the control system operates, how the postural functions are distributed within different parts of CNS, and how these parts interact with each other to produce postural corrections and adjustments. This review outlines recent advances in the studies of postural control in quadrupeds, with special attention given the neuronal postural mechanisms.
Pain, itch, heat, cold, and touch represent different percepts arising from somatosensory input. How stimuli give rise to these percepts has been debated for over a century. Recent work supports the view that primary afferents are highly specialized to transduce and encode specific stimulus modalities. However, cross-modal interactions (e.g. inhibition or exacerbation of pain by touch) support convergence rather than specificity in central circuits. We outline how peripheral specialization together with central convergence could enable spinal microcircuits to combine inputs from distinctly specialized, co-activated afferents and to modulate the output signals thus formed through computations like normalization. These issues will be discussed alongside recent advances in our understanding of microcircuitry in the superficial dorsal horn.
Glutamatergic pathways dominate information processing in the brain, but these are not homogeneous. They include two distinct types: Class 1, which carries the main information for processing, and Class 2, which serves a modulatory role. Identifying the Class 1 inputs in a circuit can lead to a better understanding of its function. Also, identifying Class 1 inputs to a thalamic nucleus tells us its main function (e.g., LGN is the relay of retinal Class 1 input), and such identification leads to a division of thalamic relays into first and higher order: the former receives Class 1 inputs from subcortical sources; the latter, from layer 5 of cortex, which it then relays to another cortical area. When a cortical area directly connects with another, it often has a parallel, transthalamic connection through these higher order relays. This leads to a novel appreciation of cortical functioning and raises many new questions.