Synaptic Plasticity in the Injured Brain Depends on the Temporal Pattern of Stimulation.

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain.

Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance.

The (histone) deacetylase Sirt1 is a mediator of genomic and epigenetic maintenance, both of which are critical aspects of stem cell homeostasis and tightly linked to their functional decline in aging and disease. We show that Sirt1 ablation in adult hematopoietic stem and progenitor cells (HSPCs) promotes aberrant HSPC expansion specifically under conditions of hematopoietic stress, which is associated with genomic instability as well as the accumulation of DNA damage and eventually results in a loss of long-term progenitors. We further demonstrate that progenitor cell expansion is mechanistically linked to the selective up-regulation of the HSPC maintenance factor and polycomb target gene Hoxa9.

A residue in loop 9 of the beta2-subunit stabilizes the closed state of the GABAA receptor.

In gamma-aminobutyric acid type A (GABA(A)) receptors, the structural elements that couple ligand binding to channel opening remain poorly defined. Here, site-directed mutagenesis was used to determine if Loop 9 on the non-GABA binding site interface of the beta2-subunit may be involved in GABA(A) receptor activation. Specifically, residues Gly(170)-Gln(185) of the beta2-subunit were mutated to alanine, co-expressed with wild-type alpha1- and gamma2S-subunits in human embryonic kidney (HEK) 293 cells and assayed for their activation by GABA, the intravenous anesthetic propofol and the endogenous neurosteroid pregnanolone using whole cell macroscopic recordings.

Inverse effects on gating and modulation caused by a mutation in the M2-M3 Linker of the GABA(A) receptor gamma subunit.

M2-M3 linkers are receptor subunit domains known to be critical for the normal function of cysteine-loop ligand-gated ion channels. Previous studies of alpha and beta subunits of type "A" GABA receptors suggest that these linkers couple extracellular elements involved in GABA binding to the transmembrane segments that control the opening of the ion channel. To study the importance of the gamma subunit M2-M3 linker, we examined the macroscopic and single-channel effects of an engineered gamma2(L287A) mutation on GABA activation and propofol modulation.

Resonance tuning of a neuromechanical system with two negative sensory feedback configurations.

Resonance tuning in a model of rhythmic movement is compared when the central pattern generator (CPG) consists of two endogenously bursting or two tonically spiking neurons that are connected with reciprocally inhibitory synapses. The CPG receives inhibitory and/or excitatory position feedback from a linear, one-degree-of-freedom mechanical subsystem. As with previously published results [5, 15], resonance tuning is limited to frequencies that are greater than the intrinsic CPG frequency with endogenously bursting neurons.

A comparison of resonance tuning with positive versus negative sensory feedback.

We used a computational model of rhythmic movement to analyze how the connectivity of sensory feedback affects the tuning of a closed-loop neuromechanical system to the mechanical resonant frequency (omega(r)). Our model includes a Matsuoka half-center oscillator for a central pattern generator (CPG) and a linear, one-degree-of-freedom system for a mechanical component. Using both an open-loop frequency response analysis and closed-loop simulations, we compared resonance tuning with four different feedback configurations as the mechanical resonant frequency, feedback gain, and mechanical damping varied.