Optogenetics, the use of microbial rhodopsins to make the electrical activity of targeted neurons controllable by light, has swept through neuroscience, enabling thousands of scientists to study how specific neuron types contribute to behaviors and pathologies, and how they might serve as novel therapeutic targets. By activating a set of neurons, one can probe what functions they can initiate or sustain, and by silencing a set of neurons, one can probe the functions they are necessary for. We here review the biophysics of these molecules, asking why they became so useful in neuroscience for the study of brain circuitry. We review the history of the field, including early thinking, early experiments, applications of optogenetics, pre-optogenetics targeted neural control tools, and the history of discovering and characterizing microbial rhodopsins. We then review the biophysical attributes of rhodopsins that make them so useful to neuroscience – their classes and structure, their photocycles, their photocurrent magnitudes and kinetics, their action spectra, and their ion selectivity. Our hope is to convey to the reader how specific biophysical properties of these molecules made them especially useful to neuroscientists for a difficult problem – the control of high-speed electrical activity, with great precision and ease, in the brain.

Background: Neuroimaging studies have revealed structural and functional changes in brain regions associated with major depressive disorder (MDD). These abnormalities appear to be more common and extensive in patients with late-life depression than in younger patients. It has therefore been hypothesized that different morphometric and pathological changes may be associated with MDD, depending on age.

Methods: This review stratifies the findings of the various studies on cell morphology in MDD according to age and assesses any possible differences in neuronal and glial cell changes in younger and older age groups.

Results: Recent morphological studies in postmortem tissue have revealed alterations in neuron and glial cell populations in the frontal and subcortical circuitry associated with depression. These may differ by age, with glial reduction consistently reported in younger groups in cortical areas and neuronal changes identified in studies with older subjects.

Conclusions: Apparent differences in the morphological changes between younger and elderly patients may suggest a differing pathological basis in MDD, dependent on age.

As the most primitive metazoan phylum, the Platyhelminthes occupies a unique position in nervous system evolution. Centrally, their nervous system consists of an archaic brain from which emanate one or more pairs of longitudinal nerve cords connected by commissures; peripherally, a diverse arrangement of nerve plexuses of varying complexity innervate the subsurface epithelial and muscle layers, and in the parasitic taxa they are most prominent in the musculature of the attachment organs and egg-forming apparatus. There is a range of neuronal-cell types, the majority being multi- and bipolar. The flatworm neuron is highly secretory and contains a heterogeneity of vesicular inclusions, dominated by densecored vesicles, whose contents may be released synaptically or by paracrine secretion for presumed delivery to target cells via the extracellular matrix. A wide range of sense organ types is present in flatworms, irrespective of life-styles. The repertoire of neuronal substances identified cytochemically includes all of the major candidate transmitters known in vertebrates. Two groups of native flatworm neuropeptides have been sequenced, neuropeptide F and FMRFamide-related peptides (FaRPs), and immunoreactivities for these have been localised in dense-cored neuronal vesicles in representatives of all major fiatworm groups. There is evidence of co-localisation of peptidergic and cholinergic elements; serotoninergic components generally occupy a separate set of neurons. The actions of neuronal substances in flatworms are largely undetermined, but FaRPs and 5-HT are known to be myoactive in all of the major groups, and there is immuno-cytochemical evidence that they have a role in the mechanism of egg assembly.

Gaining insight into how the nervous system functions is a challenge for scientists, particularly because the static morphology of the brain and the cells within tell little about how they actually work. Fixed specimens can provide critical structural information, but the jump to functional neurobiology in living cells is obviated with these preparations. In order to grasp the complexity of neuronal activity, it is necessary to observe the brain in action, from the level of subcellular signaling to the whole organism. Recent advances in nonlinear microscopy have given rise to a new era for biological research. In particular, the introduction of multiphoton excitation has drastically improved the depth and speed to which we can probe brain function. In order to better appreciate recent contributions of multiphoton microscopy to our current and future understanding of biological systems, an historical awareness of past microscopy applications is useful.

Metazoans are composed of a finite number of recognisable cell types. Similar to the relationship between species and ecosystems, knowledge of cell type diversity contributes to studies of complexity and evolution. However, as with other units of evolution, the cell type often resists definition. This review proposes guidelines for characterising cell types and discusses cell homology and the various developmental pathways by which cell types arise, including germ layers, blastemata (secondary development/neurulation), stem cells, and transdifferentiation. An updated list of cell types is presented for a familiar, albeit overlooked model taxon, adult Homo sapiens, with 411 cell types, including 145 types of neurons, recognised. Two methods for organising these cell types are explored. One is the artificial classification technique, clustering cells using commonly accepted criteria of similarity. The second approach, an empirical method modeled after cladistics, resolves the classification in terms of shared features rather than overall similarity. While the results of each scheme differ, both methods address important questions. The artificial classification provides compelling (and independent) support for the neural crest as the fourth germ layer, while the cladistic approach permits the evaluation of cell type evolution. Using the cladistic approach we observe a correlation between the developmental and evolutionary origin of a cell, suggesting that this method is useful for predicting which cell types share common (multipotential) progenitors. Whereas the current effort is restricted by the availability of phenotypic details for most cell types, the present study demonstrates that a comprehensive cladistic classification is practical, attainable, and warranted. The use of cell types and cell type comparative classification schemes has the potential to offer new and alternative models for therapeutic evaluation.

Multiple classes of precursor cells have been isolated and characterized from the developing spinal cord including multipotent neuroepithelial (NEP) stem cells and lineage-restricted precursors for neurons (NRPs) and glia (GRPs). We have compared the survival, differentiation and integration of multipotent NEP cells with lineage-restricted NRPs and GRPs using cells isolated from transgenic rats that express the human placental alkaline phosphatase gene. Our results demonstrate that grafted NEP cells survive poorly, with no cells observed 3 days after transplant in the adult hippocampus, striatum and spinal cord, indicating that most CNS regions are not compatible with transplants of multipotent cells derived from fetal CNS. By contrast, at 3 weeks and 5 weeks post-engraftment, lineage-restricted precursors showed selective migration along white-matter tracts and robust survival in all three CNS regions. The grafted precursors expressed the mature neuronal markers NeuN and MAP2, the astrocytic marker GFAP, the oligodendrocytic markers RIP, NG2 and Sox-10, and the synaptic marker synaptophysin. Similar behavior was observed when these precursors were transplanted into the injured spinal cord. Predifferentiated, multipotent NEP cells also survive and integrate, which indicates that lineage-restricted CNS precursors are well suited for transplantation into the adult CNS and provide a promising cellular replacement candidate.

This study reports Müller cell and neuronal changes and microglial reaction in streptozotocin-induced diabetic rats. Glial fibrillary acidic protein (GFAP) immunoreactivity was largely confined to astrocytes in the nerve fiber layer (NFL) and ganglion cell layer (GCL) in control rats. In diabetic rats especially those killed after 12 months, GFAP immunostaining could be traced along the entire length of Müller cell processes, extending from the inner to the outer limiting membrane. With the antibody neuronal nuclei, immunopositive cells were located in the GCL and the inner part of the inner nuclear layer (INL) in both diabetic and age-matched control rats. In diabetic rats, labelled cells were reduced in both layers being more marked in the INL. In age-matched control rats, OX42-immunoreactive microglial cells were distributed mainly in the NFL and GCL; some cells were localized in the inner plexiform layer, but rarely in the outer plexiform layer (OPL). Beginning 1 month after diabetes, the microglial cells appeared hypertrophic. Furthermore, microglial number as estimated from cell counts in different layers of the retina was significantly increased, with the occurrence of some cells in the OPL at 4 months. At 14 and 16 months, reactive microglial cells were detected in the outer nuclear layer and photoreceptor layer. Present results suggest that microglial reaction in induced diabetes was elicited by neuronal cell loss in both GCL and INL as well as by some pathologic changes affecting the photoreceptors.

We propose a model of a passive nerve cylinder undergoing random stimulus along its length. It is shown that this model is approximated by the solution of a stochastic partial differential equation. Numerous properties of the sample paths are derived, such as their modulus of continuity, quadratic and quartic variation, and it is shown that the solution exhibits the phenomenon of flicker noise. The first-passage problem is studied, and it is shown to be connected with a first-hitting time for an infinite-dimensional diffusion.