Our understanding of the cellular implementation of systems-level neural processes like action, thought and emotion has been limited by the availability of tools to interrogate specific classes of neural cells within intact, living brain tissue. Here we identify and develop an archaeal light-driven chloride pump (NpHR) from Natronomonas pharaonis for temporally precise optical inhibition of neural activity. NpHR allows either knockout of single action potentials, or sustained blockade of spiking. NpHR is compatible with ChR2, the previous optical excitation technology we have described, in that the two opposing probes operate at similar light powers but with well-separated action spectra. NpHR, like ChR2, functions in mammals without exogenous cofactors, and the two probes can be integrated with calcium imaging in mammalian brain tissue for bidirectional optical modulation and readout of neural activity. Likewise, NpHR and ChR2 can be targeted together to Caenorhabditis elegans muscle and cholinergic motor neurons to control locomotion bidirectionally. NpHR and ChR2 form a complete system for multimodal, high-speed, genetically targeted, all-optical interrogation of living neural circuits.

Multimodal fast optical interrogation of neural circuitry

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

/pdf/adult-hippocampal-neurogenesis-and-its-role-in-alzheimer-s-49j6nf9drn.pdf

Adult hippocampal neurogenesis and its role in Alzheimer's disease

Bridging animal and human models of exercise-induced brain plasticity.

The Fine Structure of the Nervous System: The Cells and Their Processes

Neural Circuitry of Wakefulness and Sleep

It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (β-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of β-amyloid plaques and an increase in the number of β-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment.

/pdf/impaired-adult-neurogenesis-in-the-dentate-gyrus-of-a-triple-3mcg7jfhjq.pdf

Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's Disease

https://www.cell.com/cell/pdf/S0092-8674(16)30404-4.pdf

Sleep Drive Is Encoded by Neural Plastic Changes in a Dedicated Circuit

Sleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability

http://ddata.over-blog.com/3/18/64/17/2014/Liu-et-al-2014.pdf

WIDE AWAKE mediates the circadian timing of sleep onset.

Free-living animals must not only regulate the amount of food they consume but also choose which types of food to ingest. The shifting of food preference driven by nutrient-specific hunger can be essential for survival, yet little is known about the underlying mechanisms. We identified a dopamine circuit that encodes protein-specific hunger in Drosophila . The activity of these neurons increased after substantial protein deprivation. Activation of this circuit simultaneously promoted protein intake and restricted sugar consumption, via signaling to distinct downstream neurons. Protein starvation triggered branch-specific plastic changes in these dopaminergic neurons, thus enabling sustained protein consumption. These studies reveal a crucial circuit mechanism by which animals adjust their dietary strategy to maintain protein homeostasis.

http://science.sciencemag.org/content/sci/356/6337/534.full.pdf

Masashi Tabuchi

Papers

Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's Disease

Sleep Drive Is Encoded by Neural Plastic Changes in a Dedicated Circuit

Sleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability

WIDE AWAKE mediates the circadian timing of sleep onset.

Branch-specific plasticity of a bifunctional dopamine circuit encodes protein hunger