Journal of Experimental Neuroscience最新文献

Birds such as the barn owl and zebra finch are known for their remarkable hearing abilities that are critical for survival, communication, and vocal learning functions. A key to achieving these hearing abilities is the speed and precision required for the temporal coding of sound-a process heavily dependent on the structural, synaptic, and intrinsic specializations in the avian auditory brainstem. Here, we review recent work from us and others focusing on the specialization of neurons in the chicken cochlear nucleus magnocellularis (NM)-a first-order auditory brainstem structure analogous to bushy cells in the mammalian anteroventral cochlear nucleus. Similar to their mammalian counterpart, NM neurons are mostly adendritic and receive auditory nerve input through large axosomatic endbulb of Held synapses. Axonal projections from NM neurons to their downstream auditory targets are sophisticatedly programmed regarding their length, caliber, myelination, and conduction velocity. Specialized voltage-dependent potassium and sodium channel properties also play important and unique roles in shaping the functional phenotype of NM neurons. Working synergistically with potassium channels, an atypical current known as resurgent sodium current promotes rapid and precise action potential firing for NM neurons. Interestingly, these structural and functional specializations vary dramatically along the tonotopic axis and suggest a plethora of encoding strategies for sounds of different acoustic frequencies, mechanisms likely shared across species.

Historically, identification of active metabolites has contributed to drug discovery for psychiatric disorders. It has led to the identification of new medications such as desipramine (a metabolite of imipramine) and paliperidone (a metabolite of risperidone). (R,S)-Ketamine, which has been regarded as the greatest breakthrough in depression research, is rapidly and stereoselectively metabolized into a variety of metabolites. Therefore, identification of an active substance after administration of (R,S)-ketamine is a critical issue, not only to delineate the underlying mechanisms but also to pave the way to develop a new antidepressant. Recently, one of the metabolites of (R,S)-ketamine, namely, (2R,6R)-hydroxynorketamine (HNK) was proposed as an active metabolite formed after administration of (R,S)-ketamine, and even as being essential for (R,S)-ketamine to exert its antidepressant effects. However, this is still controversial. Indeed, we demonstrated that the antidepressant effect of (2R,6R)-HNK is not as potent as that of its parent compounds ((R)-ketamine and (R,S)-ketamine), and that (2R,6R)-HNK is not essential for (R)-ketamine to exert its antidepressant effects. From the historical point of view, however, there is potential to discover new medications by further investigations of (2R,6R)-HNK. Therefore, more careful and thorough investigation of (2R,6R)-HNK is needed for the discovery of more efficacious and safer antidepressants.

The development of the nervous system requires precise outgrowth, extension, and wiring of both axons and dendrites to generate properly functioning neural circuits. The molecular mechanisms that shape neurite development, in particular dendritic development, remain incompletely understood. Dendrites are often highly branched and coated with actin-filled, thorny protrusions, called dendritic spines, that allow for increased numbers of synaptic contacts with neighboring neurons. Disruptions in dendritic spine development have been implicated in many neurological disorders such as autism, schizophrenia, and Alzheimer's disease. Although the development of dendritic spines is vital for cognitive function, understanding the mechanisms driving their outgrowth and stabilization in vivo remains a challenge. Our recent work identifies the presence of dendritic spine-like structures in the nematode Caenorhabditis elegans and provides initial insights into mechanisms promoting spine outgrowth in this system. Specifically, we show that neurexin/nrx-1 is a critical molecular component in directing the development of synaptic connections and promoting spine outgrowth. Our investigation provides important insights into the molecular machinery that sculpt synaptic connectivity, and continuing efforts in this system offer the potential for identifying new mechanisms governing both synaptic partner selection and dendritic spine outgrowth.

The hippocampus encodes memories for past events, but the nature of the hippocampal code subserving this function remains unclear. A prevailing idea, strongly supported by hippocampal physiology, is the Cognitive Map Theory. In this view, episodic memories are anchored to spatial domains, or allocentric frameworks, of experiences, with the hippocampus providing a stable representation of external space. On the other hand, recent studies using Immediate Early Genes (IEGs) as a proxy of neuronal activation support the Memory Index Theory. This idea posits that the hippocampal memory trace serves as an index for a cortical representation of memory (a map for internal representation) and hypothesizes the primary hippocampal function is to reinstate the pattern of cortical activity present during encoding. Our recent findings provide a unitary view on these two fundamentally different theories. In the hippocampal CA1 region the activity of c-Fos expressing pyramidal neurons reliably reflects the identity of the context the animal is experiencing in an index-like fashion, while spikes from other active pyramidal cells provide spatial information that is stable over a long period of time. These two distinct ensembles of hippocampal neurons suggest heterogeneous roles for subsets of hippocampus neurons in memory.

Taste modalities are conserved in insects and mammals. Sweet gustatory signals evoke attractive behaviors while bitter gustatory information drive aversive behaviors. Salt (NaCl) is an essential nutrient required for various physiological processes, including electrolyte homeostasis, neuronal activity, nutrient absorption, and muscle contraction. Not only mammals, even in Drosophila melanogaster, the detection of NaCl induces two different behaviors: Low concentrations of NaCl act as an attractant, whereas high concentrations act as repellant. The fruit fly is an excellent model system for studying the underlying mechanisms of salt taste due to its relatively simple neuroanatomical organization of the brain and peripheral taste system, the availability of powerful genetic tools and transgenic strains. In this review, we have revisited the literature and the information provided by various laboratories using invertebrate model system Drosophila that has helped us to understand NaCl salt taste so far. We hope that this compiled information from Drosophila will be of general significance and interest for forthcoming studies of the structure, function, and behavioral role of NaCl-sensitive (low and high concentrations) gustatory circuitry for understanding NaCl salt taste in all animals.

Real-world information is primarily sensory in nature, and understandably people attach value to the sensory information to prepare for appropriate behavioral responses. This review presents research from value-based, perceptual, and social decision-making domains, so far studied using isolated paradigms and their corresponding computational models. For example, in perceptual decision making, the sensory evidence accumulation rather than value computation becomes central to choice behavior. Furthermore, we identify cross-linkages between the perceptual and value-based domains to help us better understand generic processes pertaining to individual decision making. The purpose of this review is 2-fold. First, we identify the need for integrated study of different domains of decision making. Second, given that both our perception and valuation are influenced by the surrounding context, we suggest the integration of different types of information in decision making could be done by studying contextual influences in decision making. Future research needs to attempt toward a system-level understanding of various subprocesses involved in decision making.

Triheteromeric N-methyl-D-aspartate receptors (NMDARs) are assemblies of two different types of GluN2 subunits that endow receptors with properties distinct from their diheteromeric counterparts. Previous studies show an abundance of triheteromeric NMDARs across the central nervous system (CNS), making them an important receptor population to investigate and potential drug target. A recent study by Bhattacharya et al. (1) demonstrated the prevalence of GluN1/GluN2A/GluN2C triheteromeric NMDARs in cerebellar granule cells (CGCs), (2) suggested that GluN2C subunits seldom express as diheteromers, (3) suggested that GluN2A subunits are the preferred partners for GluN2C to functionally express at the cell surface, and (4) revealed unique single-channel properties of these triheteromeric assemblies, which may enable these cells to perform unique tasks. Taken together, this work demonstrates the physiological existence of GluN1/GluN2A/GluN2C receptors in the CGCs.

In the paper "Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo," we determined the extent of oxidative damage to specific cellular subpopulations and structures within regions vulnerable to secondary degeneration and assessed the effect this had on oligodendroglial function. Comparative assessment of oxidative damage demonstrated selective vulnerability of oligodendroglia, specifically oligodendrocyte progenitor cells (OPCs) to DNA oxidation in vivo. Immunohistochemical fate mapping along the oligodendroglial lineage showed a transient susceptibility of these cells to DNA oxidation, protein nitration, and lipid peroxidation, with mature oligodendrocytes derived immediately after injury more vulnerable to DNA oxidation than their counterparts existing at the time of injury or later derived. In situ hybridization demonstrated a reduction in myelin regulatory factor (MyRF) messenger RNA (mRNA) fluorescence in newly derived mature oligodendrocytes, suggesting a compromise in the production and maintenance of the myelin sheath in these cells. The data imply a deficit in the normal differentiation of OPCs to myelinating oligodendrocytes, associated with a transient increase in oxidative damage, which may contribute to the dysmyelinating phenotype seen at chronic time points after injury. Identifying and understanding the sources of this oxidative damage is integral for the development of therapeutic interventions for neurotrauma.

The CNTNAP2 gene has been proposed to be one of the major susceptibility genes for neurodevelopmental disorders, in which numerous heterozygous missense variants have been identified in patients with autism spectrum disorder (ASD). The contribution of these variants to the manifestations of ASD is however highly controversial because numerous heterozygous missense variants have also been identified in control subjects. In a recent study, we set up a sensitive developmental in vitro cell assay to clarify the potential functional impact of these variants in a heterozygous Cntnap2 background relevant for CNTNAP2 heterozygosity in patients with ASD. We showed that the cell adhesion glycoprotein Caspr2 encoded by CNTNAP2 plays a dose-dependent role in cortical neuron axon growth and provided a proof of principle that some variants have functional consequences, either a loss of function or a dominant-negative effect. This indicates that phenotypes mimicking CNTNAP2 heterozygous and homozygous null mutation may exist in humans. Our observations further suggest that more variants than originally expected could be functionally deleterious and induce a high heterogeneity of phenotypes at the scale of the whole brain. This raises the interesting possibility that CNTNAP2 heterozygous missense variants could define an overall endophenotype shaping a risk for ASD and questions whether, beyond ASD, the variants could contribute to the development of other neurodevelopmental disorders and/or genetically less complex pathologies.